Research Interests:
We have developed a convenient development-scale reactor (0.44 mol/h) to prepare diazomethane from N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in ∼80% yield. Diazomethane (CH2N2) made with this ...
Research Interests:
L'invention concerne des composes de mimetiques T3 contenant de l'acide phosphonique et des monoesters de ceux-ci, des stereo-isomeres, des sels pharmaceutiquement acceptables, des cocristaux et des promedicaments de ces composes,... more
L'invention concerne des composes de mimetiques T3 contenant de l'acide phosphonique et des monoesters de ceux-ci, des stereo-isomeres, des sels pharmaceutiquement acceptables, des cocristaux et des promedicaments de ces composes, ainsi que des sels pharmaceutiquement acceptables et des cocristaux de ces promedicaments. L'invention concerne egalement leur preparation et leurs utilisations pour prevenir et/ou traiter des maladies metaboliques telles que l'obesite, la steato-hepatite non alcoolique, l'hypercholesterolemie et l'hyperlipidemie, ainsi que des troubles associes comme l'atherosclerose, la maladie coronarienne, l'intolerance au glucose, le syndrome metabolique ou syndrome X et le diabete.
Research Interests:
L'invention concerne des compositions de composes antimicrobiens, des compositions pharmaceutiques, et leur utilisation et leur preparation. Dans certains modes de realisation, l'invention concerne des composes de boronate... more
L'invention concerne des compositions de composes antimicrobiens, des compositions pharmaceutiques, et leur utilisation et leur preparation. Dans certains modes de realisation, l'invention concerne des composes de boronate cycliques et leur utilisation en tant qu'agents therapeutiques.
Research Interests:
Research Interests:
In recognition of the need for effective oral therapies to treat Gram-negative bacterial infections, efforts were directed toward identifying an oral prodrug of β-lactamase inhibitor clinical candidate QPX7728. Seventeen prodrugs were... more
In recognition of the need for effective oral therapies to treat Gram-negative bacterial infections, efforts were directed toward identifying an oral prodrug of β-lactamase inhibitor clinical candidate QPX7728. Seventeen prodrugs were synthesized; key properties investigated were rates of cleavage to the active form in vitro, pharmacokinetics across species, and crystallinity. Compound 5-Na (QPX7831 Sodium) emerged with optimal properties across all key attributes.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
The present invention relates to compounds of phosphonic acid containing T3 mimetics, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the... more
The present invention relates to compounds of phosphonic acid containing T3 mimetics, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the prodrugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, metabolic syndromex and diabetes.
Research Interests:
Research Interests: Chemistry, Organic Chemistry, Medicinal Chemistry, Medicine, Mice, and 15 moreAnimals, Anti-Bacterial Agents, Boronic Acids, Rats, Carbapenems, Microbial Sensitivity Tests, Boronic Acid, In Silico, Structure activity Relationship, Pharmacophore, Beta Lactamases, Klebsiella pneumoniae, Drug synergism, Pharmacology and pharmaceutical sciences, and stereoisomerism
Sugar intermediates 4-C-methyl-2,3,5-tri-O-benzyl-d-ribofuranose (8b) and 4-C-methyl-2,3,5-tri-O-benzyl-l-lyxofuranose (8a) were synthesized by addition of alkylithium reagents to pentanones 3a,b. The nucleophilic additions proceeded with... more
Sugar intermediates 4-C-methyl-2,3,5-tri-O-benzyl-d-ribofuranose (8b) and 4-C-methyl-2,3,5-tri-O-benzyl-l-lyxofuranose (8a) were synthesized by addition of alkylithium reagents to pentanones 3a,b. The nucleophilic additions proceeded with good stereoselectivity and good yields to give the titled compounds in four steps from perbenzylated methyl d-ribofuranoside and methyl 5′-deoxy-d-ribofuranoside.
Research Interests:
Nucleosides are building blocks of life and are useful in treating infectious diseases and cancers. 1 Nucleoside based drugs are converted in the host to the active form, the nucleoside triphosphate (NTP), by enzymatic reactions that... more
Nucleosides are building blocks of life and are useful in treating infectious diseases and cancers. 1 Nucleoside based drugs are converted in the host to the active form, the nucleoside triphosphate (NTP), by enzymatic reactions that transform the nucleoside first to the ...
Research Interests:
Sequence-specific DNA ligands that antagonize DNA-protein interactions represent a potentially powerful means of modulating gene expression. Calicheamicin gamma 1I, a member of the DNA-cleaving enediyne class of anticancer antibiotics,... more
Sequence-specific DNA ligands that antagonize DNA-protein interactions represent a potentially powerful means of modulating gene expression. Calicheamicin gamma 1I, a member of the DNA-cleaving enediyne class of anticancer antibiotics, binds to specific DNA sequences through an aryltetrasaccharide domain. To take advantage of this unique sequence-specific recognition capability, the methyl glycoside of the aryltetrasaccharide of calicheamicin gamma 1I (CLM-MG) was used to investigate the ability of glycoconjugate DNA ligands to inhibit DNA-protein interactions. CLM-MG inhibits the formation of DNA-protein complexes at micromolar concentrations in a sequence-specific manner and rapidly dissociates preformed complexes. CLM-MG also inhibits transcription in vivo with similar sequence specificity. These results suggest a strategy for the development of a class of novel biological probes and therapeutic agents.
Research Interests: Biology, Medicine, Gene expression, Multidisciplinary, DNA, and 15 moreCell line, Humans, Animals, Aminoglycosides, Cell nucleus, HeLa cells, Transfection, Base Sequence, DNA binding proteins, Enediynes, Interleukin, Oligosaccharides, Carbohydrate Sequence, Molecular Sequence Data, and binding sites
We report studies of the contribution of DNA structure, holding the sequence constant, to the affinity of calicheamicin γ 1 I and its aryltetrasaccharide moiety for DNA. We used polynucleotide chains as models of known protein-binding... more
We report studies of the contribution of DNA structure, holding the sequence constant, to the affinity of calicheamicin γ 1 I and its aryltetrasaccharide moiety for DNA. We used polynucleotide chains as models of known protein-binding sequences [the catabolite activator protein (CAP) consensus sequence, AP-1 and cAMP response element (CRE) sites] in their free and protein-bound forms. The proteins were selected to provide examples in which the minor-groove binding site for the carbohydrate is (CAP) or is not (GCN4) covered by the protein. Additionally, peptides related to the GCN4 and CREB families, which have different bending effects on their DNA-binding sites, were used. We observe that proteins of the CREB class, which induce a tendency to bend toward the minor groove at the center of the site, inhibit drug-cleavage sites located at the center of the free AP-1 or CRE DNA sites. In the case of GCN4, which does not induce DNA bending, there is no effect on calicheamicin cleavage o...
Research Interests: Biology, Polysaccharides, Multidisciplinary, DNA, Protein Kinases, and 15 moreEscherichia coli, PNAS, Aminoglycosides, DNA Structure, Protein Complex Detection, Anti-Bacterial Agents, DNA binding, Base Sequence, Protein Binding, DNA binding proteins, Binding Site, Nucleic Acid Conformation, Enediynes, Oligosaccharides, and Molecular Sequence Data
Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects... more
Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects on the thyroid hormone axis (THA), muscle metabolism, and bone turnover. TR agonists selective for the TRβ isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing TRβ-mediated suppression of the THA. Herein, we describe a cytochrome P450-activated prodrug of a phosphonate-containing TR agonist that exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index. Pharmacokinetic studies in rats demonstrated that the prodrug (2 R ,4 S )-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811) undergoes first-pass hepatic extraction and that cleavage of the prodrug generates the ...
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the therapeutic index of adefovir, 1-aryl-1,3-propanyl prodrugs were... more
Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the therapeutic index of adefovir, 1-aryl-1,3-propanyl prodrugs were synthesized with the rationale that this selectively liver-activated prodrug class would enhance liver levels of the active metabolite adefovir diphosphate (ADV-DP) and/or decrease kidney exposure. The lead prodrug (14, MB06866, pradefovir), identified from a variety of in vitro and in vivo assays, exhibited good oral bioavailability (F = 42%, mesylate salt, rat) and rate of prodrug conversion to ADV-DP. Tissue distribution studies in the rat using radiolabeled materials showed that cyclic 1-aryl-1,3-propanyl prodrugs enhance the delivery of adefovir and its metabolites to the liver, with pradefovir exhibiting a 12-fold improvement in the liver/kidney ratio over adefovir dipivoxil.
Research Interests:
Research Interests: Chemistry, Organic Chemistry, Medicinal Chemistry, Pharmacokinetics, Medicine, and 15 moreDISTRIBUTION, In Vitro, Liver, Mice, Animals, Male, Hepatocellular Carcinoma, Bone marrow, High Pressure Liquid Chromatography, Hepatocytes, Medicinal, Distribution, Chemical Synthesis, Antineoplastic Agents, and Liver neoplasms
2&am... more
2'-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV) subgenomic replicon assay, by virtue of intracellular conversion to the corresponding nucleoside triphosphate (NTP) and inhibition of NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation by adenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination, we prepared cyclic 1-aryl-1,3-propanyl prodrugs of the corresponding nucleoside monophosphate (NMP), anticipating cytochrome P450 3A-mediated oxidative cleavage to the NMP in hepatocytes. Lead compounds identified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive of efficacy after intravenous dosing to rats. The oral bioavailability of the initial lead was below 5%; therefore, additional analogues were synthesized and screened for liver NTP levels after oral administration to rats. Addition of a 2',3'-carbonate prodrug moiety proved to be a successful strategy, and the 1-(4-pyridyl)-1,3-propanyl prodrug containing a 2',3'-carbonate moiety displayed oral bioavailability of 39%.
Research Interests: Chemistry, Organic Chemistry, Medicinal Chemistry, Medicine, Hepatitis C, and 15 moreAdenosine, Prodrugs, Liver, Animals, Hepatitis C Virus, Phosphorylation, Prodrug, Organophosphorus Compounds, Bioavailability, Hepatocytes, Medicinal, Organophosphates, Biological Availability, Antiviral Agents, and Pharmacology and pharmaceutical sciences
Research Interests:
Research Interests: Medicine, Prodrugs, Liver, Mice, Animals, and 15 moreMale, Hepatocellular Carcinoma, Drug Delivery Systems, Prodrug, High Pressure Liquid Chromatography, Cell Proliferation, Nucleosides, Cell Survival, Antineoplastic Agents, Drug treatment, Thymidine, Vidarabine, Tissue distribution, Liver neoplasms, and Pharmacology and pharmaceutical sciences
Research Interests:
Research Interests:
ABSTRACT In calichearubicin B (1) the aglycon of daunorubicin and the carbohydrate domain of calicheamicin γ are linked by a spacer (calichearubicin A lacks this spacer). The aglycone serves as an anthracycline-like intercalator, while... more
ABSTRACT In calichearubicin B (1) the aglycon of daunorubicin and the carbohydrate domain of calicheamicin γ are linked by a spacer (calichearubicin A lacks this spacer). The aglycone serves as an anthracycline-like intercalator, while the carbohydrate portion binds to the minor groove of DNA. Thus calichearubicin B exhibits properties of both parent compounds.