11

Chemistry in the
Pharmaceutical Industry
Graham S. Poindexter,* Yadagiri Pendri,**
Lawrence B. Snyder,* Joseph F? Yevich" and
Milind Deshpande***

INTRODUCTION been written and spoken in the lay media

This chapter will discuss the role of chemistry about the high prices of prescription drugs
within the pharmaceutical industry. Although and the hardships this places upon the elderly
the focus will be upon the industry within the and others of limited income. Consequently,
United States, much of the discussion is some consumer advocate groups support
equally relevant to pharmaceutical companies governmental imposition of price controls,
based in other first world nations such as such as those that exist in a number of other
Japan and those in Europe. The major objec- countries, on ethical pharmaceuticals in the
tive of the pharmaceutical industry is the United States.
discovery, development, and marketing of However the out-of-pocket dollars spent
efficacious and safe drugs for the treatment of by patients on prescription drugs must be
human disease. Of course drug companies do weighed against the more costly and
not exist as altruistic, charitable organizations unpleasant alternatives of surgery and hospi-
but like other share-holder owned corpora- talization, which are often obviated by drug
tions within our capitalistic society must therapy. Consideration must also be given to
achieve profits in order to remain viable and the enormous expense associated with the
competitive. Thus, there exists a conundrum development of new drugs. It can take 10
between the dual goals of enhancing the qual- years or more from the laboratory inception
ity and duration of human life and that of of a drug to its registrational approval and
increasing stock-holder equity. Much has marketing at an overall cost which is now
$600-800 million dollars and increasing.
Only 1 out of 10 to 20,000 compounds pre-
"Bristol-Myers Squibb Company, Wallingford, CT.
pared as drug candidates ever reach clinical
**Expicor, Inc., Hauppauge, NY testing in man and the attrition rate of those
***Achillion pharmaceuticals, New Haven, CT. that do is >80 percent. The expense of

404
 CHEMISTRY I N THE PHARMACEUTICAL INDUSTRY 405

developing a promising drug grows steadily A major consequence of the financial and
the further through the pipeline it pro- logistical impediments to the successful
gresses; clinical trials can be several orders introduction of new drugs has been the high
of magnitude more costly than the preclini- incidence of mergers and acquisitions among
cal evaluation of a compound. While the U.S.-based pharmaceutical companies in the
sales of successful drugs that run the gaunt- recent past. These events have not occurred
let and reach the shelves of pharmacies can because bigger is necessarily better but
eventually recoup their developmental because the critical mass of internal resources
expenses many times over, the cost of the required to bring a drug from the test tube to
drugs that fail is never recovered. the pharmacy continues to grow. In contrast to
To a large extent, the difficulties associ- this trend among the major drug companies
ated with bringing a drug to market have (often dubbed big pharma) there has been a
arisen from the increasingly stringent but proliferation of start-up companies often
appropriate criteria that have been imposed founded by entrepreneurial scientists with
by the Food and Drug Administration big pharma or academic experience and
(FDA) in the United States and analogous financed by venture capital investment. While
regulatory agencies in other countries. It is many such start ups are strictly bio-techs, oth-
unlikely that an occurrence like that of the ers function as mini drug companies and are
thalidomide disaster, which resulted in horri- staffed by both chemists and biologists.
ble birth defects several decades ago, would Unlike their much larger brethren, the small
happen again today. Furthermore the era of companies cannot attempt to cover the breath
easy approval of me-too drugs is long past. of drug research but instead focus upon a
During this era, which prevailed until the particular therapeutic area and perhaps even a
final two decades of the past century, it was particular disease. Their mission is to discover
possible to gain approval for drugs which, drug candidates, which a large company may
although they fell outside the scope of the be interested in licensing and developing.
patents covering a particular marketed drug, The big pharma companies do not rely
offered little advantage over the marketed exclusively upon filling their developmental
agent. It is now necessary for a company to pipelines with drug candidates that have been
demonstrate that a drug, for which a New discovered in-house but often enter into
Drug Application (NDA) is submitted to the collaborations and licensing agreements to
FDA, affords significant benefits in terms acquire the rights to promising agents from
of efficacy and/or safety relative to the exist- the labs of smaller companies or academic
ing drug therapy. The approvability bar may researchers.
be lowered for agents aimed at the treatment
of life-threatening maladies such as cancer
M E DlCl N A L CHE MlSTRY
and AIDS or for those such as Alzheimers
disease where no effective therapy currently Chemistry has long been an integral part of
exists; but even in these cases it is incum- the pharmaceutical industry and its impor-
bent upon the sponsoring company to pro- tance should not diminish. Many currently
vide compelling empirical evidence that marketed drugs such as the antineoplastic
their drug is safe and effective. The restric- agent, paclitaxel, and the antibiotic, van-
tions imposed by Health Maintenance comycin, are natural products. The extracts
Organizations (HMOs) can also have signif- of plants and marine organisms and the
icant impact on the sales of any given drug. products of soil bacteria fermentation will
Most HMOs list only a select few drugs, continue to be investigated as potential
for which they will cover costs, within sources of powerful new drug substances.
any given category, such as antidepressants, Chemists are certainly involved in this
antihypertensives, or cholesterol-lowering arena of drug discovery as they conduct
agents. the painstaking isolation, purification, and
406 KENTAND RIEGELS HANDBOOK OF INDUSTRIAL CHEMISTRY AND BIOTECHNOLOGY

structural characterization of pharmacologi- the medicinal chemist to know what structural

cally active components which most often components act as pharmacophores in exist-
are present in minute amounts in the natu- ing drugs. Pharmacophores, which can be of
ral source and which have extremely com- varying complexity, comprise the essential
plex chemical structures. The enormous structural elements of a drug molecule that
advances in molecular biology have enable it to interact on the molecular level
resulted in the successful development of with a biological macromolecule such as a
bio-engineered therapeutic agents, for receptor or enzyme and thus impart a phar-
example, human insulin, Herceptin macological effect. The medicinal chemist
(Genentech drug for breast cancer), and must become skilled at analyzing the struc-
Enbrel (Immunex drug for rheumatoid ture activity relationships (SAR) that pertain
arthritis). It is anticipated that many other to the series of compounds on which helshe is
biomolecules may be forthcoming for the .working. That is, how does the activity in a
treatment of human disease. biological test of analogs within the series
However the great majority of existing change depending on the introduction of
drugs are small organic molecules (MW substituents of various size, polarity, and
-200-600) that have been synthesized by lipophilicity at various domains of the parent
medicinal chemists. There is no reason to drug molecule? Elucidation of the SAR
doubt that most drugs of the future will also within a series of active compounds is the key
fall in this category. It is thus important to to optimizing the potency and other desirable
define what is meant by medicinal chemist biological properties in order to identify a
and what role is played by the practitioners of new chemical entity (NCE) as a bona fide
this sub-discipline in the pharmaceutical drug candidate. Quantitative structure activity
industry. A traditional and perhaps somewhat relationships (QSAR) are often employed in
narrow definition of medicinal chemist is that this effort; analyses employing linear free
of a researcher engaged in the design and syn- energy relationships, linear regression, and
thesis of bioactive molecules. As part of their other techniques can be utilized to correlate
academic training many medicinal chemists biological activity with the electronic, steric,
carried out doctoral and postdoctoral work polarizability, and other physicallchemical
that involved the total synthesis of natural parameters of the substituent groups on
products andor the development of synthetic members of a series of structurally related
methodology. They are hired by pharmaceuti- compounds.
cal companies because of the skills they have The synthesis and isolation of pure enan-
gained in planning and conducting the tiomers has become increasingly important.
synthesis of organic compounds. While such In the past chiral drugs were most often
skills can remain important throughout marketed as racemic mixtures since it was
chemists careers, they alone are insufficient not deemed cost-effective to provide them
for the challenging task of drug discovery in enantiomercially pure form. However, in
in which, unlike the academic environment, many cases one or the other enantiomers of an
synthetic chemistry is just a means to an end optically active drug may have a significantly
rather than an end in itself. Thus, the enter- greater level of the desired biological activity
prising young chemical researcher who enters and/or less side effect liability than its
the industry must be able and willing to antipode. Regulatory agencies such as the
undergo an evolution from that of pure FDA now routinely require that each enan-
synthetic chemist who knows how to make tiomer of a chiral drug be isolated and
compounds to that of medicinal chemist who evaluated in tests of efficacy, side effects,
also has an insight into what to make and why. and toxicity. If one of the enantiomers is
Such insight is gained by acquiring an shown to be clearly superior then it is likely
expanded knowledge base. It is important for that it is the form that will be developed as the
 CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY 407

drug candidate. Thus enantioselective chemi- disease. In many cases, X-ray crystallography
cal reactions which can afford a high enan- has provided a detailed three-dimensional
tiomeric excess(ee) of one or the other of a structure of a macromolecule such as an
pair of enantiomers are valuable components enzyme with andfor without a bound sub-
of the medicinal chemists synthetic tools. strate. Researchers having expertise in com-
Enzyme chemistry plays a prominent role in puter assisted drug design (CADD) can depict
drug R&D since isolated enzymes or microor- the determined structure on silicon graphics
ganisms can often achieve an enantiospecific terminals and in collaboration with medicinal
chemical transformation much more effi- chemists can propose drug molecules to fit
ciently and economically than conventional the active site. Such detailed analysis of
synthetic methods. Many big pharma protein structure was instrumental in the
companies now have dedicated groups that design of a number of drugs that inhibit HIV
exclusively study enzymatic reactions. protease, an enzyme essential to the integrity
of the AIDS virus.
Up until now there have been approximately
Research Strategies
1000 human proteins identified as potential
The discovery of new drugs may occur by targets for drug intervention in various
luck or serendipity or as the result of some diseases. It is estimated that the determination
brilliant insight. However pharmaceutical of the human genome will increase this num-
companies cannot depend on chance occur- ber by at least tenfold. Therefore, it seems
rences as a research strategy. The aforemen- safe to predict that the rational approach to
tioned me-too approach has hardly been drug discovery will grow accordingly and
abandoned and it is likely that the marketing with it the role of synthetic/medicinal chem-
of a novel drug will soon be followed by a istry. There will be intense competition within
number of competitors agents but with the the pharmaceutical industry to determine the
caveat that the latter offer some therapeutic functional relevance of this multitude of new
advantage over the prototype. targets in the absence and presence of disease
The most scientifically sound approach is and a close nexus to this quest will be the
that of rational drug design, which is based on search for compounds that can impart selec-
an understanding of the biochemical mecha- tive pharmacological effects upon the target
nisms underlying a particular disease. If, for proteins. But it is not likely that these
example, overactivity or underactivity of a goals can be met by employing only the
certain neurotransmitter system is believed to classical iterative approach which entails one-
be responsible for a central nervous system compound-at-a-time synthesis and low
(CNS) disorder such as depression, then volume testing. Instead the challenges of this
medicinal chemists can endeavor to design exciting new era of research must be met by
agents capable of normalizing neurotransmis- methodologies that can synthesize and test
sion by their action upon the receptor proteins large numbers of compounds in a short period
through which interneuronal communication of time-that is, combinatorial chemistry and
is mediated. Cloning and expression of high-throughput screening (HTS). In the
human genes to afford functional receptors context of its application within pharmaceuti-
and enzymes that can be studied in cell cal research, combinatorial chemistry should
culture has been a tremendous advance in the not be regarded as a separate discipline but
ability to evaluate drug action at the molecu- instead as a technologically specialized part
lar level. Likewise, molecular biology has of medicinal chemistry. This topic will be
afforded macromolecules that are essential to discussed in detail in a later section of the
the life cycle of pathogens such as bacteria chapter.
and viruses, thus enabling novel mechanistic Another important interface occurs with
strategies for the treatment of infectious chemists in process research and development.
408 KENTAND RIEGELS HANDBOOK OF INDUSTRIAL CHEMISTRY AND BIOTECHNOLOGY

In most cases medicinal chemists are not in vivo testing in some appropriate animal
overly concerned with the cost, toxicity, or model. In vivo tests are more laborious and
environmental impact of the starting materi- costly but are necessary to establish that a
als, reagents and solvents they employ to drug is effective in an intact living organism;
synthesize target compounds since they are they can range from complex behavioral par-
dealing with relatively small quantities of adigms for CNS drugs to enhancement of sur-
materials. Neither are reaction conditions vival time of tumor-implanted mice by
employing very low or elevated temperatures experimental cancer drugs. Evaluation of a
and pressures problematic on the discovery NCEs propensity to cause side effects is as
scale. However these and other pragmatic important as efficacy testing. Even if a com-
considerations must be taken into account for pound shows an encouraging level of the
the bulk scale preparation of experimental desired activity, a lack of selectivity can cause
drugs. Process chemists must very often mod- it to induce a number of undesirable pharma-
ify the synthetic procedures of their medicinal cological effects thus precluding its further
chemistry colleagues and in many cases development. The medicinal chemist must be
devise an entirely new synthetic pathway. able to interpret the results of the tests run on
Process chemistry will also be discussed in an hidher compounds and use this information
ensuing section. as a guide to further synthetic work.

Pharmacodynamics P h a r m a c o k in e t ics a n d Tox ic it y

Medicinal chemists must be generally knowl- It is also necessary that chemists are attuned
edgeable about pharmacodynamics, that is, to various aspects of pharmacokinetics (PK),
the effect of drugs upon biological systems. In that is, the effects of biological systems upon
addition to being aware of the state-of-the-art drugs. These aspects-absorption, distribu-
understanding of the biological mechanisms tion, metabolism and excretion (ADME)-
that underlie the particular diseases for are as critical as biological activity in
which they are endeavoring to discover drug determining whether a NCE is a viable drug
therapy they should know the basis of the candidate. A compound may exhibit high
various in vitro and in vivo tests that the biol- affinity for a biological receptor or potent
ogists employ to evaluate both the potential inhibition of an enzyme in an in vitro assay
efficacy and side-effect liability of the syn- but if it is poorly absorbed or rapidly metabo-
thesized compounds. Because drug research lized to inactive species then it will be inef-
covers a plethora of human diseases, each fective as a drug. For example, the empirically
with its own unique combination of etiology based Lipinskys rules of five (Table 11. l )
and biochemical mechanisms, the number define the limits of such physical/chemical
and diversity of biological tests are far too parameters as molecular weight, lipophilicity,
great to discuss in this chapter. Suffice it to
say that in a general sense the primary and TABLE 11.1 Lipinskis Rules for Drug
often even the secondary biological tests of Absorption
drugs for a particular disease target are
in vitro tests that can be run rather quickly, Absorption of a drug following oral administration is
favored by:
inexpensively, and on small amounts of com- Molecular weight is <500
pound. For example, these can be receptor The drug molecule has <5 hydrogen bond donors
binding assays for CNS drugs, enzyme assays The drug molecule has <10 hydrogen bond acceptors
for antihypertensive agents, inhibition of bac- The distribution coefficient, log P, is <5
terial colony growth by antibiotics, and the Source: Lipinski, C. A,, Lombardo, E, Dominy, D. W.,
killing of cultured cancer cells by oncolytic and Feeny, P. J., Adv. Drug Delivery Rev., 23, 3-25
drugs. Encouraging in vitro results lead to (1997).
 CHEMISTRY I N THE PHARMACEUTICAL INDUSTRY 409

and hydrogen bond forming moieties that day by devising and implementing structural
must be considered for the absorption of modifications to eliminate the toxicity. This
orally administered drugs. A compound with may be a more daunting task than overcoming
potent intrinsic activity can be rendered a side effect or metabolic issue, especially if
ineffective in vivo by its rapid conversion the toxicity is mechanism-based.
to inactive metabolites. The susceptibility of
compounds to metabolic conversion can be
Drug Delivery
assessed by incubating them with liver
homogenates from various species including Drugs can be administered to patients in many
rodent, dog, monkey, and man or with cloned, ways. The most common and preferred route is
expressed human hepatic enzymes. Analysis oral administration and oral drugs are generally
of the incubates by liquid chromatography/ formulated as tablets or capsules in which a
mass spectometry .(LC/MS) can quantify the specific dose of the drug substance is homoge-
extent of metabolism and even identify some neously mixed with some inert filler or excipi-
specific metabolites. In vivo adminstration of ent. Some oral medications, such as pediatric
a NCE to one or several animal species is formulations of antibiotics, are in solution
required to determine its oral bioavailability, form, as are injectable drugs. Obviously this
half-life, and other PK properties such as dis- requires satisfactory solubilization of the drug,
tribution and elimination. If an unsatisfactory preferably in aqueous medium. Compounds
PK profile threatens to be the demise of an bearing some ionizable group such as a basic
otherwise promising drug candidate, it falls amine or an acidic function can usually be con-
upon the medicinal chemist to make structural verted into water-soluble salts but neutral mol-
permutations aimed at correcting the prob- ecules present greater difficulties. In some
lem. If poor absorption is the problem this cases the results of clinical trials will indicate
may entail modifying the lipophilicity of that an experimental injectable drug shows
the drug molecule to render it more mem- promise of efficacy but does not elicit a robust
brane permeable. A metabolic liability might response because its poor solubility limits the
be rectified by blocking the site of biotrans- amount that can be administered and thus does
formation with a metabolically inert atom or not allow adequate plasma levels to be attained.
group. Inadequate membrane permeability can restrict
Toxic effects upon blood or organs or the the absorption and bioavailability of an orally
potential to cause gene aberrations will red administered drug.
flag a compound regardless of its having both Medicinal chemists can respond to such
excellent biological activity and PK proper- findings by investigating the feasibility of
ties. Promising lead compounds are screened preparing a suitable prodrug. A prodrug is a
in in vitro tests in bacteria and mammalian derivative in which a cleavable solubilizing
cells to determine whether they cause gene group is covalently appended to the parent
mutations and DNA damage. If they pass this drug molecule, most often via a hetero atom
hurdle the compounds are dosed on a daily such as oxygen or nitrogen. An effective pro-
basis for several weeks to several months in drug is one which has much higher solubility
both a rodent and nonrodent (usually dog than the parent drug and which following its
or monkey) species and the animals are administration is rapidly cleaved in vivo to
observed for any adverse effects; the test ani- achieve a therapeutically beneficial plasma
mals are necropsied following conclusion of concentration of the parent drug.
the study to ascertain whether any organ or
tissue damage occurred. Unacceptable toxico-
Patents
logical findings will invariably kill a drug
candidate and again it is the medicinal Patent protection on both its approved and
chemist who will be called upon to save the experimental drugs is of critical importance to
410 KENTAND RIEGELS HANDBOOK OF INDUSTRIAL CHEMISTRY AND BIOTECHNOLOGY

a pharmaceutical company. Issued patents patent will be awarded to the party that can
provide the company with exclusivity for the prove that it had the earliest conception and
manufacture, use, and sale of its drug products reduction to practice of the subject matter.
and it is highly unlikely that a company would Therefore it is imperative that chemists main-
undertake the risks and costs of developing an tain accurate records of all experimental work
agent for which it had no patent protection. in a bound notebook and that such records are
There are several types of patents of which the dated, signed, and witnessed.
composition of matter (COM) or product Other types of drug-related patents include
patent may be deemed to have the greatest process, use, and formulation patents. Chemists
value. An approved COM patent covers specif- are responsible for process patents, which
ically claimed compounds of a certain struc- describe an improved method of preparation
tural chemotype and provides empirical of some drug substance but are minimally
evidence that the claimed compounds have ,involved with the others. Use patents are
been prepared, characterized, and found to have based on the discovery of some unobvious
some utility. In order to be patentable the com- utility of a compound that is either part of the
pounds must have structural novelty and cannot public domain or covered by an existing
have been publicly disclosed either in the sci- patent; such discoveries are most likely to be
entific or patent literature or by a presentation. made by biologists. Formulation patents dis-
But structural novelty alone is not sufficient close a preferred means of drug delivery of a
grounds for a patent; it must be demonstrated known drug substance.
that the compounds are useful and in the con-
text of a drug patent the proposed utility is for
Clinical Trials
the treatment of some disease. The basis of
such utility is activity in appropriate and rele- Even though there is no involvement of chem-
vant biological tests. Clinical data may also be istry in the clinical evaluation of drugs, any
used in support of a patent application although discussion of the pharmaceutical industry
in the great majority of cases the applications must include clinical trials for the results of
are filed well before any compound within the such trials determine whether or not an exper-
application reaches clinical trials. imental drug has the combination of efficacy,
Medicinal chemists are closely affiliated safety, and tolerability which will allow it to
with the patent process and are most com- achieve registrational approval and reach the
monly the inventors listed on COM patents market. If a drug candidate survives the hur-
covering drug substances. The chemists and dles of pharmacological, pharmacokinetic,
other researchers with whom they collaborate and toxicological testing, the next customary
must provide the chemical and biological step in the United States is the sponsoring
data for the patent and the chemists will also firms filing of an Investigational New Drug
provide input as to the scope and claims of (IND) application with the FDA. This is a for-
the patent. Since patents are legal documents mal request to initiate clinical investigation in
that provide the assignee exclusive propri- man and is accompanied by a detailed
etary rights to the covered subject matter for description of the planned studies and clinical
20 years from the date of the patents issue, protocols. Upon approval of the IND, Phase I
it is essential that all supportive data be clinical studies are initiated.
accurate and instructive. If a patent is ever Phase I studies are conducted in healthy
challenged by another party and is found to volunteers in order to establish the drugs
contain erroneous information then it safety and to determine appropriate dosage
could be invalidated. Moreover, in the levels. If the drug is found to have an accept-
United States, patents are granted on a first- able human pharmacokinetic profile and to
to-invent basis. Thus if two or more parties be free of untoward side effect liabilities, it
submit applications on identical subject is advanced into Phase I1 trials, which are
matter to the U.S. Patent Office then the typically carried out in several hundred
 CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY 41 1

patients and may last from six months to then medicinal chemists will endeavor to
two years. Phase I1 trials are designed to design and prepare an analog with improved
ascertain the appropriate dosing regimen for pharmacokinetic properties.
the drug and whether it is effective in treat-
ing the target disease. Only about one third
Summary
of drugs pass Phase I1 trials, most failing
because of the lack of efficacy. Those that The preceding sections present what is an
pass are advanced into Phase I11 trials which admittedly superficial overview of the very
may involve from several hundred to several extensive and complex topic of medicinal
thousand patients and which can last from chemistry, its role in the pharmaceutical indus-
one to three years or even longer depending try, and its interface with other disciplines. An
on the type of drug under study and the acquired understanding of relevant biology,
complexities of the study design. Phase I11 pharmacology, toxicity, and so on is not just of
trials provide the ultimate test of an experi- heuristic value but is necessary for the chemist
mental drug since they are designed to verify to engage in meaningful dialogue with their
the drugs effectiveness against the target colleagues who work in these specialties.
disease as well as its safety. For agents that Successful drug discovery and development
are intended for chronic use, studies also cannot be done by individuals working in iso-
monitor adverse reactions that may develop lation but requires the interactive collaboration
only after long-term use and the develop- of many researchers representing a multiplicity
ment of tolerance. Clinical studies of many of scientific disciplines as depicted in
drug classes will commonly employ several Fig. 11.1. It may be argued that medicinal
patient groups of approximately equal size chemists are the most versatile generalists
with one group receiving the experimental among these researchers in that they must have
drug, another placebo (nondrug), and primary expertise in chemistry along with
another a positive control, that is, a marketed extensive knowledge of numerous other areas.
drug used to treat the same disease for which The following section presents examples
the experimental agent is being evaluated. In of marketed drugs in a number of different
order to minimize the possibility of bias in therapeutic categories.
favor of the test drug, such studies are most
often run in a double-blinded manner with
neither patients nor clinical investigators CARDIOVASCULAR AGENTS
knowing which group is receiving which
Hypertension
treatment until the conclusion of the trial.
If a drug candidate is among the one in four A variety of agents of several mechanistic
to five that gets through Phases 1-111 and if types are currently available for the treatment
statistical analysis of the clinical data sup- of hypertension (elevated blood pressure).
ports its efficacy then the sponsoring firm The dihydropyridine derivative amlodipine
will assemble the voluminous data into the (NorvascE/Pfizer) is a receptor-operated,
NDA which is submitted to the FDA. Review calcium entry blocker that prevents Ca++
of the NDA can take one to two years and entry into vascular smooth muscle cells.
often the FDA may request that additional Amlodipine is also useful for the treatment of
information be provided or even that some angina. Losartan (Cozaar5/Merck) and irbe-
additional studies be done. When approval is sartan (AvaproE/Bristol-Myers Squibb) are
granted the company is then free to market angiotensin receptor antagonists that inhibit
the drug. the action of angiotensin I1 on the AT, recep-
The results of clinical evaluation of an exper- tor. Metoprolol (Toprola/AstraZeneca) is a
imental drug can feed back into medicinal cardioselective, p, -adrenergic receptor block-
chemistry. For example, if a drug is found to ing agent and is also useful in the treatment of
fail because of poor bioavailability in humans angina.
412 KENTAND RIEGELS HANDBOOK OF INDUSTRIAL CHEMISTRY A N D BIOTECHNOLOGY

\
n-Bu
amlodipine losartan

\
n-Bu
rnetoprolol
irbesartan

Congestive Heart Failure, Migraine, and receptors (most likely the 5-HT1,! and 5-HT,,
Thrombolytic Agents
subtypes) in the vasculature. It is thought to
Enalapril (Vasotek@/Merck) and lisinopril exert its beneficial effects on migraine
(Zestril@/AstraZenecaand Prinvil@/Merck)are headaches by selective constriction of certain
angiotensin-converting enzyme (ACE) large cranial blood vessels andor possibly
inhibitors, useful in the treatment of congestive through suppression of neurogenic inflamma-
heart failure and hypertension by suppression tory processes in the central nervous system.
of the renin-angiotensin-aldosterone system. Clopidogrel (Plavix@/Bristol-Myers Squibb,
Enalapril is an ethyl ester prodrug that is Sanofi-Synthelabo) is an inhibitor of ADP-
hydrolyzed in the liver to the active carboxylic induced platelet aggregation and is usehl in
acid enalaprilat. Sumatriptan is a selective ago- the treatment of various thrombolytic events
nist of serotonin (5-hydroxytryptamine) type- 1 such as stroke and myocardial infarction.

+ //
4QO2H
enalapril, R = C02Et
enalaprilat, R = C02H lisinopril

S;02Me

sumatriptan
clopidogrel
 CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY 413

Historical
Compound

Process
Evaluation Chemistry

ceutical

Clinical

Fig. 11.1. Drug discovery and development is a complicated process that involves the interaction of
researchers in various disciplines. Medicinal chemists may synthesize analogues based on chemical leads
arising from the high throughput screening of combinatorial libraries or historical compound inventories.
Alternatively, analogue synthesis can be based on the collaboration between medicinal chemistry and
computer-assisted drug design to rationally design small molecules capable of interacting with a macro-
molecular biological target (receptor or enzyme). Subsequent biological, pharmacokinetic, and toxico-
logical avaluations lead to identification of a drug candidate that, following development of a suitable
bulk scale synthesis by process chemistry and pharmaceutical formulation, is advanced into clinical tri-
als. Feedback to medicinal chemistry from any of these developmental steps can give rise to further syn-
thetic modifications and refinements.

METABOLIC AGENTS glutaryl-CoA (HMG-CoA) reductase inhibitors

(statins) that lower serum lipid levels by
Hyperlipidemia
inhibiting cholesterol biosynthesis. Simvastatin
Simvastatin (Zocor@/Merck), pravastatin and pravastatin are semi-synthetic, mevinic
(Pravachol@/Bristol-Myers Squibb), atorvas- acid-derived antilipidemic agents whereas
tatin (Lipitor@/Pfizer), and rosuvastatin atorvastatin is a wholly synthetic, pentasubsti-
(Crestor@/ AstraZeneca) are hydroxymethyl- tuted pyrrolo heptanoic acid. Unlike pravas-
414 KENTAND RIEGEL'S HANDBOOK OF INDUSTRIAL CHEMISTRY AND BIOTECHNOLOGY

tatin, atorvastatin, and atorvastatin, simvas- Plough and consists of a mixture of simvas-
tatin is a lactone prodrug which must be con- tatin and ezetimibe in one pill.
verted to the corresponding, ring-opened
6-hydroxy acid in vivo. A newer agent with a Diabetes
novel mechanism of action is ezetimibe
(Zetia@/Merck,Schering Plough). Ezetimibe A variety of mechanistic agents are currently
does not inhibit cholesterol biosynthesis in available for the treatment of type 2 (noninsulin-
liver as do the statins but rather inhibits cho- dependent) diabetes mellitus (NIDDM)].
lesterol absorption in the intestine. This novel Rosiglitazone (AvandiaB/GlaxoSmithKline)
action is complementary to the HMG-CoA is a thiazolidinedione (glitazone) antidiabetic
reductase mechanism displayed by the agent and an agonist at the peroxisome prolif-
statins. An innovative new product for the erator-activated receptorgamma(PPARgamma).
treatment of hyperlipidemia is Vytorina. It ,Activation of this receptor enhances insulin
was developed by Merck and Schering sensitivity in target tissues by increasing

Et*
0 "qrO
Me Me&Me Me

Me" HO'

si rnvastatin pravastatin

Ca++

atorvastatin
- 2
rosuvastatin

ezetirnibe
 CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY 415

insulin-responsive gene transcription. Met- GASTROINTESTINAL AND

formin (GlucophageD/Bristol-Myers Squibb) G E NI T 0 uRI NARY AGENTS
is an antihyperglycemic agent that improves Antisecretory
glucose tolerance in patients with type 2
diabetes. The compound acts by decreasing Ranitidine (ZantacD/GlaxoSmithKline) is a his-
both hepatic glucose production and intestinal tamine H,-receptor antagonist that inhibits the
absorption of glucose, and improves insulin release of gastric acid and is useful in the treat-
sensitivity by increasing peripheral glucose ment of a variety of hypersecretory conditions
uptake and utilization, Glimepiride (Amaryl@/ [dyspepsia, and gastric
Aventis) is in the sulfonylurea class of antidi- ulcers, and gastroesophageal reflux (GERD)].
abetic agents. Glimepiride is thought to lower Lansoprazole (PrevacidE/TAP), omeprazole
blood glucose concentration by stimulating (PrilosecE/AstraZeneca), and esomeprazole
insulin secretion in pancreatic beta cells. (Nexium@/AstraZeneca) are benzimidazole

Me2N XNYNH2
Me H

rosiglitazone metformin

o"i;b
glimepiride

gastric antisecretory agents and unrelated both

Obesity chemically and pharmacologically to the H,-
Orlistat (XenicalE/Roche) is a reversible gastric receptor antagonists. These agents are known
and pancreatic lipase inhibitor. The compound as proton pump inhibitors due to their ability to
has no effect on appetite suppression but rather inhibit the H'K+-ATPase (the proton pump) in
acts by inhibiting dietary fat absorption from gastric parietal cells thereby blocking the
the GI tract. Sibutramine (Meridia@/Abbott) secretion of hydrochloric acid. Esomeprazole
and its major active metabolites are re-uptake is the S-enantiomer of omeprazole which is
racemic and thus a mixture of both its R-and
M e y o i-Bu
' L

0 NMe2
Me

orlistat sibutramine

inhibitors of norepinephne, serotonin, and S-enantiomers. Lansoprazole and omeprazole

dopamine and exert their beneficial effect are also useful in the management of duodenal
through appetite suppression. and gastric ulcers, and GERD.
416 KENTAND RIEGELS HANDBOOK OF INDUSTRIAL CHEMISTRY A N D BIOTECHNOLOGY

u
NHMe
:F,
ranitidine Mk bJ
lansoprazole

orneprazole

Benign Prostatic Hypsrplasia syncope). Because doxazosin is not selective

and Urinary Urge Incontinence for the a,,-subtype, it is also useful in
Doxazosin (CarduraE/Pfizer), tamsulosin the treatment of hypertension. Finasteride
(Flomax/Boehringer Ingelheim), and alfu- (Proscar@/Merck) and dutasteride (AvodartB/
zosin (Uroxatrala/Sanofi-Synthelabo) are GlaxoSmithKline) are 5a-reductase inhibitors
used in the management of benign prostatic that block the conversion of testosterone to
hyperplasia (BPH). The compounds are post- 5a-dihydrotestosterone (DHT). Because DHT
synaptic, a ,-adrenergic blocking agents that is an androgen responsible for prostatic
relax prostatic tissue and increase urinary out- growth, inhibition of the 5a-reductase enzyme
flow in men. Because tamsulosin demon- is beneficial in reducing prostatic enlargement.
strates selectivity for the a ,,-adrenergic
receptor subtype located in prostate over that
Erectile Dysfunction
of a,,-subtype located in vascular tissue,
there is a reduced incidence of cardiovascu- The pyrazolopyrimidinone derivative silde-
lar side effects (hypotension, dizziness, and nafil (ViagraB /Pfizer), the indolopyrazinone

sildenafil
OZSQEt

vardenafil
,.Me

tadalafil
 CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY 417

derivative tadalafil (CialisE /Lilly ICOS), and blood-brain barrier, it is considered a nonse-
the imidazotrizinone derivative vardenafil dating antihistamine. More recently, the qua-
(Levitra@/Bayer) are selective inhibitors of the ternary ammonium tricyle tiotropium bromide
phosphodiesterase (PDE) type 5 enzyme. (SpirivaE/Boehringer-Ingelheim/Pfizer) has
They act by selectively blocking the PDE type been introduced. It is a long-acting bron-
5 isoenzyme ultimately causing vascular chodilator useful in the treatment of asthma
vasodilation in corpus cavemosal tissue and exerts its pharmacological effect through
which, in turn, leads to penile tumescence and inhibition of the muscarinic M, receptor.
rigidity.
INFLA MM A T I0 N A ND 0ST E 0 P0 R0S IS
PULMONARY AGENTS
Arthritis
Asthma and Allergic Rhinitis
The diary1 pyrazole derivative celecoxib
Fluticasone (Flovent@/GlaxoSmithKline)is a (CelebrexE/Pharmacia, Pfizer), the furanone
synthetic corticosteroid derivative that is a derivative rofecoxib (VioxxE/Merck), and the
selective agonist at the human glucocorticoid isoxazole derivative valdecoxib (Bextra/

Me Br-
Me-N

fluticasone fexofenadine M Me tiotropium bromide

receptor and useful in the treatment of Pfizer) are selective cyclooxygenase type 2
asthma. Although the precise mechanism of (COX-2) inhibitors and are useful in the treat-
fluticasone in asthma is unknown, it is ment of arthritis. The compounds exert their
believed its anti-inflammatory property con- pharmacological effect by selectively block-
tributes to its beneficial effect. The buty- ing the COX-2 enzyme to produce an anti-
rophenone derivative fexofenadine (Allegra@/ inflammatory effect without adverse
Aventis) is an antihistamine and used in the gastrointestinal side effects. In addition, they
treatment of seasonal allergic rhinitis. Because also display analgesic and antipyretic activi-
fexofenadine does not readily cross the ties in animal models.

celecoxib rofecoxi b valdecoxib

418 KENTAND RIEGEL'S HANDBOOK OF INDUSTRIAL CHEMISTRY AND BIOTECHNOLOGY

Osteoporosis
The benzothiophene derivative raloxifene
(EvistaR/Lilly) is a selective estrogen receptor
modulator (SERM). Raloxifene produces
its biological actions via modulation (both
activation and blockade) of estrogen receptors fluoxetine
that ultimately results in decreased resorption
of bone. The bisphosphonate derivative alen-
dronate (Fosamax@/Merck), an inhibitor of

%
osteoclast-mediated bone resorption, is also
useful in the treatment of osteoporosis. Both
raloxifene and alendronate are useful in the
treatment of osteoporosis in postmenopausal
women.
'CI CI

sertraline

raloxifene
'-0 no) 0

i
, )
H
P03H' Na+
paroxetine
alendronate

CENTRAL NERVOUS SYSTEM AGENTS

Antidepressants
Fluoxetine (Prozac@/Lilly), paroxetine
(Paxil@/GlaxoSmithKilne), and sertraline venlafaxine
(ZoloftE/Pfizer) are selective serotonin
reuptake inhibitors (SSRIs) and are useful
Anxiolytics
in the treatment of depression. These agents
potentiate the pharmacological actions of Alprazolam (Xanax@/Pharmacia),a benzodi-
the neurotransmitter serotonin by prevent- azepine derivative is used for the treatment of
ing its reuptake at presynaptic neuronal both anxiety and panic disorder and buspirone
membranes. In addition to its SSRI proper- (Buspar@/Bristol-Myers Squibb) is indicated
ties, venlafaxine (Effexor@/Wyeth-Ayerst) for the treatment of anxiety disorders. The
also appears to be a potent inhibitor of neu- mechanism of action of buspirone is distinct
ronal norepinephrine reuptake and a weak from that of the benzodiazepines and is
inhibitor of dopamine reuptake thereby believed to be mediated mainly through mod-
enhancing the actions of these neurotrans- ulation of serotonergic neurotransmission via
mitters as well. Venlafaxine is indicated for its interaction with the 5-HT,, serotonin
use in anxiety and depression. receptor subtype.
 CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY 419

CI a
3 -N

alprazolam buspirone

Bipolar Disorders, Schizophrenia, of epilepsy. Although structurally related to

and Epilepsy GABA, it has no GABA-ergic activity. The
The thienobenzodiazepine derivative olanzap- mechanism for its anticonvulsive actions is
ine (Zyprexa@/Lilly), and benzisoxazole currently unknown.
risperidone (Risperidal@/Janssen)are atypical
antipsychotic agents. Olanzapine is used in Alzheimers Disease
the treatment of bipolar disorder and risperi-
The indanone derivative donepezil (Aricept@/
done is useful in the management of schizo-
Pfizer, Eisai) is an acetycholinesterase
phrenia. It is believed that both compounds
inhibitor and is structurally unrelated to other
exert their beneficial effects through antago-
cholinesterase inhibitors. Because it
nism of serotonergic and dopaminergic recep-
increases the concentration of the neuro-
tors. A newer agent for the treatment of
transmitter acetycholine at cholinergic sites,
schizophrenia is aripiprazole (AbilifyB/
it is useful in the treatment of Alzheimers
Bristol-Myers Squibb, Otsuka). It is believed
the pharmacological effects are mediated disease (dementia). Another agent useful in
the treatment of Alzheimers disease is the
through a combination of partial agonist
adamantly1 amine derivative memantine
activity at the dopamine D, and serotonin 5-
(Namenda@/ Forest). Memantine is a N-
HT,, receptors and antagonism at the serotin-
methyl-D-aspartate (NMDA) receptor antag-
ergic 5-HT2 receptor. The y-aminobutyric
acid derivative (GABA) gabapentin onist and is thought to exert its
pharmacological effect by blocking the
(Neurontin@/Pfizer) is useful in the treatment

Me
olanzapine risperidone

aripiprazole gabapentin
420 KENTAND RIEGELS HANDBOOK OF INDUSTRIAL CHEMISTRY AND BIOTECHNOLOGY

excitatory action of the amino acid gluta- many bacterial infections. Amoxicillin/
mate on the receptor. Memantine has shown Clavulanate is one of the few approved drug
no evidence of preventing or slowing neu- mixtures and is a drug of choice for the treat-
rodegenaration in Alzheimers patients. ment of otitis media. It is also an alternative

Me0 6
Me
memantine
Me

donepezi

INFECTIOUS DISEASES treatment for anthrax exposure in pediatrics.

Ciprofloxacin is a totally synthetic antibacter-
Antibacterials ial that acts as a DNA gyrase inhibitor. It is
The primary driver for research in the anti- active against a broad range of pathogens
bacterial area over the past decade has been including both gram-positive and gram-
the emergence of resistant organisms. negative aerobic bacteria and is effective
Important members of the ever-growing against urinary tract and lower respiratory
armamentarium of antibacterials include tract infections. Linezolid is a totally syn-
azithromycin (Zithromax@/Pfizer), linezolid thetic oxazolidinone derivative which has a
(Zyvox@/Pharmacia),amoxicillin / clavulanate unique mechanism of action resulting in a low
potassium (Augmentina/GlaxoSmithKline), potential for cross resistance to other antibac-
ciprofloxacin (Cipro@/Bayer)and daptomycin terials. Linezolid is indicated for the treat-
(CubicidCubist). Azithromycin is a semisyn- ment of community acquired pneumonia,
thetic 9a-azalide analog of erythromycin pos- MRSA, and VRE infections and has the dis-
sessing improved resistance to acid-mediated tinctive characteristic of being 100% orally
degradation, increased activity against gram- bioavailable. Daptomycin (Cubicin@/Cubist),
negative organisms, and improved pharmaco- a cyclic lipopeptide of molecular formula
kinetics. Its indications include the treatment C,,H,,,N,,O,,, is a bactericidal antibacterial
of mild to moderate upper and lower respira- agent used for the treatment of infections
tory tract infections and otitis media in pedi- caused by gram-positive bacteria including
atrics. Interestingly, azithromycin tends to those that are resistant to standard antibacter-
concentrate in lung tissue which is the site of ial regimens.

HO
A

amoxicillin / clavulanic Acid ciprofloxacin

 CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY 421

%
OH Me -?I
0

az ithromycin linezolid

Antifungals HIVIAIDS, Hepatitis B and C, and RSY

The increasing immunocompromised patient Indinavir (Crixivan/Merck) is one of a group
population has exacerbated the need for of HIV protease inhibitors and is used in con-
effective antifungal agents to combat oppor- junction with other antiretroviral chemothera-
tunistic hngal infections that arise in these peutic agents for the treatment of AIDS in
patients. Fluconazole, an achiral triazole deriv- adults and adolescents. It is a Phe-Pro scissile
ative, is indicated for the treatment of sys- bond peptidomimetic with a hydroxyindane
temic candidiasis as well as meningitis caused moiety that was optimized for selectivity and
by Cryptococcus neoformans. Itraconazole potency. More recently, atazanavir sulfate
(Sporanox@/Janssen, Ortho Biotech), a mix- (Reyataz@/Bristol-Myers Squibb) was intro-
ture of four diastereomers, is used to treat duced as the latest protease inhibitor. Clinical
aspergillosis, oral canchdiasis, and histoplas- data suggests that atazanavir may have a more
mosis. These agents are structurally related to favorable hypertriglyceridemia profile as
other imidazole-based antifungals such as compared to other protease inhibitors.
ketoconazole and miconazole but have better Ribavirin (RebetronE/Schering Plough and
antihngal activity and broader coverage. Virazole/ICN) is a synthetic nucleoside

CI
/

fluconazole itraco nazo le

Antivirals
used to treat respiratory syncytial virus
Antiviral research has become a major focus (RSV) in hospitalized infants and is also used
in the pharmaceutical industry over the past in combination therapy with interferon for
decade as evidenced by the marketing of a the treatment of chronic hepatitis C.
plethora of antiviral agents active against Efavirenz (Sustiva8/Bristol-Myers Squibb) is
422 KENTAND RIEGEL'S HANDBOOK OF INDUSTRIAL CHEMISTRY A N D BIOTECHNOLOGY

a synthetic nonnucleoside reverse transcrip- Tamoxifen (Nolvadexa/AstraZeneca), a nons-

tase inhibitor (NNRTI) used in conjunction teroidal antiestrogen chemotherapeutic pos-
with other antiretroviral agents for the treat- sessing both agonistic and antagonistic
ment of HI\! properties, is used for the treatment and preven-

indinavir ribavirin

CI
0
\0 A
d
w efavirenz

atazanavir

ANTINEOPLASTICS
tion of breast cancer. Imitanib (Gleevac@/
Paclitaxel (Taxol@/Bristol-MyersSquibb) and Novartis), an inhibitor of Bcr-Abl tyrosine
irinotecan (CamptosaraiPharmacia) were dis- kinase recently received FDA approval for the
covered as a result of natural product extract treatment of chronic myelogenous leukemia.
screening done at the NIH in the late 1960s by Bortezomib (VelcadeE/Millenium and Ortho
Monroe Wall and Mankush Wani. Paclitaxel is Biotech), an iv ubiquitin proteosome inhibitor,
a naturally occurring diterpene that exerts its is used for the treatment of multiple myeloma
antineoplastic effect via stabilization of the in pateints who have been refractory to
mitotic spindle during cell replication. It is used other chemotherapeutic regimens. Cetuximab
for the treatment of nonsmall cell lung, breast, (Erbitux@/ImClone,Merck KGaA, and Bristol-
ovarian, and esophageal carcinomas as well as Myers Squibb) a human-murine chimeric mon-
Kaposi's sarcoma. Irinotecan is a prodrug that oclonal antibody that blocks the epidermal
upon release of the piperidinylpiperidine carba- growth factor receptor (EGFR), was developed
mate moiety reveals the pharmacologically for the treatment of irinotecan-refractory col-
active parent SN-38 which is itself a derivative orectal cancer. This agent is also used in
of the naturally occurring camptothecin. patients who are irtolerant of irinotecan-based
Irinotecan exerts its antineoplastic activity via therapy. The small molecule EGFR tyrosine
the inhibition of Type I DNA topoisomerase kinase inhibitor gefitinib (IressaB/Astra-
and stabilization of the transiently formed Zeneca) is used to treat nonsmall cell lung
Topoisomerase I/DNA cleavable complex. cancer.
 CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY 423

HO

HN-(
F- 0

Ph- -( 'Ph
0
Ph

paclitaxel irinotecan

Me

imat i nib bortezornib

NMe2

tamoxifen gefitinib

MISCELLANEOUS AGENTS prostaglandin PGF2a and is thought to

reduce intraocular pressure by increased out-
Glaucoma and Nausea
flow of the aqueous humor. Odansetron
Latanoprost (Xalatan$/Pharmacia & Upjohn) (Zofrana/GlaxoSmithKline) is a selective,
is a topical, ocular hypotensive agent used to serotonergic, 5-HT3receptor antagonist and is
treat glaucoma. The compound is a syn- used to ameliorate nausea and vomiting asso-
thetic analogue of the naturally occurring ciated with chemotherapy-induced emesis.
424 KENTAND RIEGELS HANDBOOK OF INDUSTRIAL CHEMISTRY AND BIOTECHNOLOGY

Me\

HO
he
latanoprost
odansetron

Propoxyphene Aspirin Acetominophen Ibuprofen

Me0
NH2
doxazosin tamsulosin

Me

alfuzosin tolterodine

&NHt-Bu

0 N i
H H

finasteride dutasteride
 CHEMISTRY I N THE PHARMACEUTICAL INDUSTRY 425

in 1992. Since then, small molecule library gies utilize resin-based split-pool synthesis to
synthesis has affected drug discovery efforts prepare large arrays of compounds. Libraries
in lead identification, as well as lead opti- of >50K members were prepared by using
mization. In a recent review, R. Dolle has cat- chemically encoded beads. Chemical encryp-
egorized synthetic libraries as follows: (1) tion, in the form of unique chemical markers
discovery libraries: libraries synthesized with (tags), is associated with synthetic identity of
no preconceived notion about which molecu- the library member tethered to the resin bead.
lar target it may be active against. These The technology for chemical encoding was
libraries tend to be large in size, typically pioneered by W. Clark Still and subsequently
>5000 compounds.(2) targeted libraries: commercialized by Pharmacopeia, Inc.
these libraries are biased in their design and Restricted amount (200-300 pg), lack of ana-
contain a pharmacophore known to interact lytical characterization of library members,
with a specific target, or a family of tar- and the requirement of a specialized screen-
gets.(3) optimization libraries: libraries are ing format for chemically encoded libraries
constructed around an existing lead with the have limited the utility of this technology.
intent to improve potency, selectivity, phar- Radio-frequency encoded synthesis, devel-
macokinetic profile, etc. These libraries tend oped and commercialized by IRORI, Inc.
to be smaller in size, usually ranging from overcomes the afore mentioned limitations
tens up to a few hundred compounds. while retaining the efficiency of split-pool
synthesis. Libraries of 10-1 5K members can
be prepared, with individual members quanti-
Discovery Libraries tated and characterized by LC/MS. Most
Researchers have employed several different pharmaceutical companies have utilized Rf-
strategies to create populations of molecules encoded synthesis in their lead identification
that are used for broad-based screening. One efforts.
strategy is to synthesize libraries of privi-
leged pharmacophores such as benzodi-
Targeted Libraries
azepines (l), triazines (2), and so on. A
second strategy is to design scaffolds or tem- Libraries targeted towards proteolytic enzymes,
plates for library synthesis that are based on nonproteolytic enzymes, G-protein coupled
important molecular recognition. Libraries receptors (GPCRs) and ion-channels have
of p-turn mimetics ( 3 ) synthesized by been very successful in lead identification.
Ellman et al. are examples of templates for Libraries of hydroxamates (4), hydroxy ethyl-
molecular recognition. enes (5), boronic acids ( 6 ) and crketo sulfon-

R4 R

1 2 3

The discovery of chemical encoding tech- amides (7) have been prepared as inhibitors of
nologies and radio-frequency (Rf) encoded metallo-, aspartyl, serine and cysteine pro-
synthesis have had a major impact on synthe- teases respectively, using either solid phase or
sis of lead discovery libraries. Both technolo- solution phase synthesis.
426 KENTAND RIEGEL'S HANDBOOK OF INDUSTRIAL CHEMISTRY AND BIOTECHNOLOGY

4 5

6 7

Structure-based design has been effectively targeted libraries. A combination of cation

utilized in synthesis of inhibitors of non- exchange (SCX) and anion exchange (SAX)
proteolytic enzymes. Inhibitors of MurB, an resin was effectively utilized to prepare
essential bacterial enzyme required for libraries of highly substituted amides.
biosynthesis of peptidoglycan, were identi- Scavenger resins and polymer-bound reagents
fied using the X-ray structure of the enzyme are routinely used to prepare medium-sized
for library design. Thiazolidinone inhibitors (500-1 000 member) libraries. Polymer-bound
(8) thus identified are the first examples of isocyanates (9) and aldehydes (10) are used to
small molecule inhibitors of MurB. remove amines from reaction mixtures, while
polymer-bound thiols (1 1) are used to scav-
enge halides.

Substituted indoles (5HT,,; D4 and aZa

receptor antagonists) and piperazines (6 opiod
antagonists) are representative chemotypes
targeted towards GPCRs.
Advances made in solid phase extraction Optimization Libraries
(SPE) and in develoDment of resin-based
. I

scavengers have increased the versatility of Starting with a lead structure, researchers
chemistries implemented for synthesis of have demonstrated that parallel synthesis can

i) SAX
RqCOOX + RZRSNH b R,CONR,R,
ii) SCX
 CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY 427

be effectively utilized to optimize activity, as CHEMICAL PROCESS R&D IN THE

well as reduce timelines for optimization. PHARMACEUTICAL INDUSTRY
Parallel synthesis strategy was implemented Most of the active pharmaceutical ingredients
to identify more potent analogs of influenza (APIs) of commercially available pharmaceu-
hemagglutinin inhibitor (12) (IC50= 4 pgiml). ticals are manufactured either by chemical
Solid phase extraction was used to automate syntheses or microbial fermentations. However,
preparation of >400 analogs resulting in some of the active ingredients are directly
identification of compounds (13) (IC50 = 20 obtained from natural sources. This section
ngiml) and (14) (IC5,, = 20 ng/ml). addresses the development and manufacture

During the past 10 years, the pharmaceutical of APIs. Recent trend shows that >75 percent
industry has expended significant resource in of the drug candidates in development are
developing and assimilating technologies to chiral and of complex structure. Incessant
increase synthesis throughput and decrease demand to shorten the timelines for the dis-
preclinical time lines. There are numerous covery, development and launch of NCEs
examples in the literature demonstrating effec- coupled with environmental concerns has
tive use of high throughput synthesis for lead necessitated the development of higher yield-
discovery and optimization. There are two ing, more robust and environmentally friendly
publicly known examples of clinical candi- processes in shorter times. The success of a
dates that have emerged directly from opti- pharmaceutical company greatly depends not
mization libraries. Ontogen Corporation only on discovering blockbuster NCEs but
identified OC144-093, (15) (IC50 = 50 nM) as also on its ability to design, optimize and
a P-glycoprotein modulator and Agouron scaleup a chemical process to commercial
Pharmaceuticals reported identification of manufacturing with increasing rapidity. The
AG-7088, (16) (kobJI = 1,470,000 M- S - ) , chemical manufacturing process must be a
a clinical candidate for treatment of rhinovirus robust procedure capable of operating rou-
infection. tinely in a manufacturing environment.
428 KENTAND RIEGELS HANDBOOK OF INDUSTRIAL CHEMISTRY AND BIOTECHNOLOGY

Considerable attention has to be given to mization and production planning activities

various parameters in developing a manufac- need to be addressed. Production simulation
turing process for an API, including for can be used for performance measurements
example: efficiency of the synthesis, avail- and capacity assessments of manufacturing
ability and cost of starting materials, toxicity as well as material and information flow
of the reagents, stability and toxicity profiles processes. Some applications of production
of intermediates, formation of byproducts, simulation include bottleneck analysis,
and safe disposal of waste materials. Data examination of process alternatives, assess-
from various aspects of chemical process ment of investment decisions and solution of
development, including process structure sequencing problems. Batch process devel-
and flowsheet, operational guidelines, opti- opment is a fairly complex series of engi-
mization, process management, process con- neering tasks. In the pharmaceutical
trol, fault diagnostics and equipment ,industry, the production of a majority of
management need to be in place in order to APIs is based on a batch concept. This con-
support a smooth transition from laboratory cept offers many advantages with respect to
to manufacturing plant. Safety is another quality assurance as an individual batch can
critical factor requiring consideration for be accepted or rejected. However, the scale-
large-scale manufacture. All reactions up of the batch size without proper controls
should undergo a process hazard analysis for may lead to problems. The variety of the
incident-free and successful plant implemen- equipment involved often does not facilitate
tation before scale-up. The use of automa- the scale-up process. In order to avoid scale-
tion in accelerating the design of up problems, continuous or semi-continuous
cost-effective and well-understood synthetic processes need to be adopted as alternatives
processes has been demonstrated over the to a batch production.
past few years by pharmaceutical companies Crystallization, filtration, drying and
and a few research groups in academia and is milling (if required) are other important
now beginning to grow very rapidly. factors that need to be defined well before a
Automation concepts and tools such as sta- process to manufacture solid APIs is final-
tistical design of experiments and parallel ized. Physicochemical properties of APIs
experimentation using in-house built reactor play a vital role in providing the pharma-
blocks or commercially available systems ceutical drug products with desired
such as Zymark robots, ReactArray, Bohdan, bioavailability, manufacturing properties,
Argonauts Surveyor, or Mettler Toledo and good final product quality. Particle
MultiMax will play a major role in increas- size, density, flowability, polymorphism,
ing the productivity of process R&D with hygroscopicity, and stability are critical
respect to speed and economics, as well as properties for solid APIs in the formulation
obtaining process knowledge. The applica- development. Polymorphism is very impor-
tion of microreaction technology (micropi- tant in determining the physical properties
loting) is another area that is growing rapidly of various crystal forms of a drug for opti-
to understand the chemical engineering mal chemical and formulation processing,
aspects of process development. Some bene- as well as for satisfying regulatory and
ficial features of microreaction technology patent issues for producing consistent solid
include mixing efficiency, enhanced heat forms of a drug.
transfer, and more uniform residence time The following flow diagrams show the
distributions. preparation of APIs of some widely used
Production and logistical processes are pharmaceutical drugs in todays market.
becoming more complex due to an increas- Scheme-1 shows the preparation of sildenafil.
ing number of products and smaller batch This route has a greater synthetic conver-
sizes. To manage this, supply chain opti- gency than other published routes.
 CHEMISTRY IN THE PHARMACEUTICAL INDUSTRY 429

Scheme-1

PH 1. CIS03H

2. SOCI,
OH 1. N-rnethylpiperzine*

H 2 0 / NaOH
rNy&
Me/ N J
0, P
-0Et
N/-7
W N

S0,CI 2. CDI, EtOAc

17 18 9

K O B /~'BUOH
Pd-C
HCI
O2N H, 5Opsi H2NH2N
%Ne
n-Pr n-Pr
H2N%i 20 21
0 Ye

n-Pr
Me/ OEt

sildenafil

Synthesis of fluoxetine as a racemic mix- The single enantiomer of indinavir has five
ture is shown in scheme-2. Recently several stereogenic centers, four of which are derived
patents and publications have appeared in the either directly or indirectly from epoxide (27).
literature describing the synthesis of ( S ) - and Synthesis of indinavir sulfate developed by
( R) enantiomers. Merck is shown in Scheme-3.

Scheme-2

aCHo 0

AOEt

LHMDS
e o i : HNMe
#NHMe

22 23 24

LiAIH4 &NHMe 1.4-CF3C6H4C!

NaH

2. HCI F 3 C Q o L NHMe
25 HCI
fluoxetine
 430 KENTAND RIEGEL'S HANDBOOK OF INDUSTRIAL CHEMISTRY AND BIOTECHNOLOGY

Scheme-3

(S,S,)-Mn(ll)(Salen)
0.7 mol%
Aq. NaOCl
Oleurn
a NHz
IIOH
1. PhCHZCHzCOCI
NaOH, HzO

2. 2-Methoxypropene
MsOH
c

26 27 28

1. NCS, Nal
$? Ally1 bromide
2. NaOMe

29
30 31

Nq
N , &
tBUOAc, HzS04 HN

Hz, Pd(OH), *
1
CNH
(s)-pyroglutamicacid

BoczO, KOH
I. CH,OH
2. HCI (gas)

.HzS04
35
indinavir

greater benefit-to-risk ratios than those cur-

CONCLUSION rently available. The elucidation of the human
The discovery and development of novel ther- genome will eventually lead to the identifica-
apeutic agents by the pharmaceutical industry tion of many new macromolecular targets for
has afforded physicians an extensive arma- drug intervention. Chemistry has been and
mentarium to fight a wide range of human will likely continue to remain at the forefront
disease. Of course there remains the opportu- of pharmaceutical research which will afford
nity for even more effective drugs with the drugs of the future.

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