Prayuth Poowaruttanawiwit, Int J Pharm 2018; 8(1): 58-61 ISSN 2249-1848

International Journal of Pharmacy

Journal Homepage: http://www.pharmascholars.com

Short Communication CODEN: IJPNL6

Concepts for Alzheimer’s Disease Drug Development

Prayuth Poowaruttanawiwit*

Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University,

Phitsanulok, Thailand

*Corresponding author e-mail: yuth_pu@hotmail.com

Received on: 04-01-2018; Revised on: 05-01-2018; Accepted on: 08-01-2018

INTRODUTION

Alzheimer’s disease (AD) was a neuronal disease with no effectively stop or even slow down the disease progression.
completely cure drug [1,2]. Patient with AD suffer from [6,7]. However, it is not easy to discover or synthesis the drug
symptoms which required closely attention [2-5]. The which combines the appropriate characteristics that enables to
important limitations of management include lacking of act in multi modes of pathogenic sites, exhibits excellent
good and practical diagnostic methods and insufficient efficacy and safety characteristics in the unique molecule and
choice in medications. The crucial barriers to the discovery displays the properties of oral absorption drug and appropriate
or synthesis of effective drug for treatments of AD characteristics of CNS drug in the unique molecule (Table 1).
including AD are caused by integration and simultaneous These obstacles have raised the inspiration that if there is a
occurrence of several complex pathologies in the patient’s new drug candidate that demonstrates features of multi-
brain treating at a single pathology is inadequate to targeting action and good safety, it could be an alternative
choice for Alzheimer’s treatment.

Table 1: Properties for oral absorption drug and appropriate characteristics of CNS drug

Lipinski Rules of Five [8] Appropriate CNS Drug Characteristics [9]

1. Its molecular weight is less than 500. 1. Molecular weight ≤ 400

2. The compound's lipophilicity, expressed as a quantity known 2. Log P ≤ 5

as log P (the logarithm of the partition coefficient between
water and 1-octanol), is less than 5.

3. The number of groups in the molecule that can donate 3. Hydrogen bond donor ≤ 3
hydrogen atoms to hydrogen bonds (usually the sum of
hydroxyl and amine groups in a drug molecule) is less than 5.

4. The number of groups that can accept hydrogen atoms to form 4. Hydrogen bond acceptor ≤ 7
hydrogen bonds (estimated by the sum of oxygen and nitrogen

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Prayuth Poowaruttanawiwit, Int J Pharm 2018; 8(1): 58-61 ISSN 2249-1848
atoms) is less than 10.

5. Number of rotatable bonds ≤ 10

Cholinesterase inhibitors (donepezil, galantamine and numerous of significance studies and it was involved from the
rivastigmine) and NMDA receptor antagonists (memantine) beginning of the disease through the late stage (Figure 1).
have been approved for treatment AD for more than three Although, this hypothesis was considered as a long-standing
decades [10]. They have been limited to being single theory, recent studies [11-15] has shown some connections
pathogenic mechanism drugs, for symptomatic use, being suggesting that the notions of cholinergic theory could be
insufficient for use in the severe disease stages and cannot improved and should be adapted in further Alzheimer’s drug
directly achieve results at the disease’s origins [2,3]. developments (Table 2). Consistent with this current informatio,
Cholinergic hypothesis still has been accepted as the well- the cholinergic postulation is still an important target of AD
known pathogenic mechanism which has been supported by development (Table 3).

Figure 1: Changes of cholinergic functions with aging and Alzheimer’s disease

Note: Decline of cholinergic signals involve with aging and AD at the onset through the late stage of disease. Intracellular oxidative
stress and neuro inflammation cause cholinergic cells death and lead AD patient undergo the severe disease stage.

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Prayuth Poowaruttanawiwit, Int J Pharm 2018; 8(1): 58-61 ISSN 2249-1848
Table 2: The traditional versus more recent concepts of cholinergic hypothesis and the expected characteristic of the novel Alzheimer’s drug replacement

The Traditional Concept More Recent Concepts Expected Characteristic of the Novel Alzheimer’s Drug
Candidate
Alzheimer’s symptoms caused by the Many studies [17-19] have raised the impression that if a Non-selective AChE and BuChE inhibitor
reduction of acetylcholine levels in large number of AChE were used to hydrolyze
patient’s brain [16]. Acetylcholine is acetylcholine, it would be the reason for BuChE increasing,
destroyed by AChE which is the target therefore the entire cause was still not completely
of existing drugs [14]. terminated. In addition, in studies [12-14] of Alzheimer’s
patients it has been observed that there is a decrease of
AChE and increase of BuChE levels.
The studies [20-22] proposed that AChE also demonstrates Inhibit the AChE-Aβ complex formation by inhibit the
a non-cholinergic function which attaches to Aβ at the PAS activity of AChE at PAS
of the AChE and forms to be the AChE-Aβ complex. This
complex is shaped together in the brain and is described as a
neurotoxic agent. Latest pharmacological data expressed
that the AChE-Aβ complex displayed more neurotoxicity
than Aβ alone [23,24]. Additionally, the AChE in the
complex is still function [22].

Table 3: The traditional versus more recent concepts of cholinergic hypothesis and the expected characteristic of the novel Alzheimer’s drug replacement (Cont.)

The Traditional Concept More Recent Concepts Expected Characteristic of the Novel
Alzheimer’s Drug Candidate
The inhibition of AChE and BuChE can reduce oxidative Protect the neuronal cells from oxidative stress
stress through the cholinergic anti-inflammatory pathway and neuro-inflammation
[25, 26]. The mechanism of this pathway is the increasing of
acetylcholine neurotransmitters and maintains the viability of
healthy neurons, which indirectly preserve neuronal cells
from oxidative stress destruction [26].

In summary, the cholinergic theory is clearly indicated to be challenge question is raised that is it better if we have a drug
a main target of Alzheimer’s treatment, and the recent candidate which acts as a multi targeting agent and safes to use
additional knowledge of AChE-Aβ complex formation can be in human?
applied to the design a candidate for treatment of AD. The

REFERENCES

1. Alzheimer's association Chicago (2014). Major milestones in Alzheimer’s and Brain Research [Internet]: Retrieved
December 28, 2017, from:http://www.alz.org/research/science/major_milestones_in_alzheimers. asp.
2. G. Waldemar, B. Dubois, M. Emre., Europ. J. Neuro. 2017, 14-26.
3. J. Hort, J. T. Brienb, G. Gainotti, T. Pirttila, B. O. Popescu, I. Rektorova., Euro. J. Neuro. 2010, 17, 1236-1248.
4. W. Z. Carolyn, S. Mary., Clin. Interve. Agi. 2016, 1(2), 143-154.
5. M. Fernanda, V. M. Paula, F. V. Luciane, S. S. Franklin, V. F. Orestes, S. Y. Mônica., Deme. Neuropsycho. 2009, 3(3), 241-
247.
6. S. M. Ann, L. Constantine., J. Advan. Nur. 2005, 3(8), 256-270.
7. J. C. Rudy, Z. Xiongwei, G. L. Hyoung, A. S. Mark, P. George., Inter. J. Mole. Sci. 2009, 10, 1386-1406.
8. C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney., Advan. Dr. Del. Rev.1997, 23, 3-25.

60
Prayuth Poowaruttanawiwit, Int J Pharm 2018; 8(1): 58-61 ISSN 2249-1848

9. P. Hassan, R. L. George., Neur. Res. 2005, 2, 541-553.

10. Alzheimer's association. (2012) FDA-approved treatment for Alzheimer’s. [Internet]. Retrieved December 18, 2017. From:
http://www.alz.org/national/documents/topicsheet_treatments.pdf.
11. R. Schliebs, T. Arendt., J. Neu. Trans. 2006, 113, 1625-1644.
12. J. M. Elliott, E. C. Scott, E. P. Sylvia, D. G. Stephen., Ex. Rev. Neurothera. 2008, 8(11), 1703-1718.
13. N. H. Greig, D. K. Lahiri, K. Sambamurti., Intern. Psychoger. 2002, 14, 77-91.
14. E. A. Margaret, M. Brendan., J. Neuro. Neurosur. Psyc. 1992, 55, 1074-1078.
15. F. J. Carvajal , N. C. Inestrosa., J. Mol. Neurosci. 2011, 4-19.
16. G. Johnson, S. W. Moore., Cur. Pharma. Des. 2006, 12, 217-225.
17. A. V. Terry, J. J. Buccafusco., J. Pharma. Expe. Thera. 2003, 306, 821-827.
18. Z. X. Shen., Med. Hypot. 2004, 63, 308-321.
19. C. D. Magarita, P. S. Juan, A. Q. Rodrigo, A. G. Juan, S. A. Macarena, C. I. Nibaldo., Implication for the pathogenesis of
Alzheimer’s disease Molecular Neurodegeneration, 2010, 5, 4.
20. C. Guiquan, Z. Xiaoyan, W. Hirotaka, M. D. Jan, S. Jie S., J. Neurosci. 2010, 30(33), 13066-13077.
21. G. Ezio., Pharma. Res. 2004, 50, 433-440.
22. V. F. Giancarlo, A. C. Mauricio, S. Irina, M. W. Lev, S. Israel, C. I. Nibaldo., Biochem. 2001, 40, 10447-10457.
23. A. Alejandra, O. Carlos, A. Rodrigo, G. Jorge, C. Nibaldo., J. Mol. Bio. 1997, 272, 346-361.
24. T. Rees, P. I. Hammond, H. Soreq, S. Younkin, S. Brimijoin., Neurobio. Agi. 2003, 24, 777-787.
25. A. P. Valentin, W. Hong, J. C. Chistopher, G. F. Steven, Mol. Med. 2003, 9, 125-133.
26. Miroslav P., Inter. J. Mol. Sci. 2014, 15, 9809-9825.

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