Biomedical Chemistry: Research and Methods, 2018, 1(3), e00015
The 40th Anniversary of the Institute of Physiologically Active Compounds of the Russian Academy of Sciences

Current Trends in the Development of Drugs for the Treatment of Alzheimer’s Disease
and their Clinical Trials

S.O. Bachurin, E.V. Bovina*, A.A. Ustyugov

Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severny proezd, Moscow region, Chernogolovka, 142432 Russia,*e-mail: bovina_e@ipac.ac.ru

Key words: Alzheimer’s disease; neurodegenerative diseases; multitarget compounds; disease-modifying drugs; repositioning of drugs

DOI: 10.18097/BMCRM00015

The whole version of this paper is available in Russian.

Intracellular and extracellular accumulation of fibrillary proteins, beta-amyloid and hyperphosphorylated Tau, in patients with Alzheimer’s disease (AD) leads to chronic and progressive neurodegenerative process. Overaccumulation of aggregates results in synaptic dysfunction and inevitable neuronal loss. Although the exact molecular pathways of the AD still require better understanding, it is clear this neuropathology is a multifactorial disorder where the advanced age is the main risk factor. Lately, several dozens of drug candidates have succeeded to phase II clinical trials; however, none has passed phase III. In this review we summarize existing data on anti-AD therapeutic agents currently undergoing clinical trials and included in the public websites www.clinicaltrials.gov and Alzforum.org as well as the Thomson Reuters «Integrity» database. We revealed three major trends in AD drug discovery. First, developing of “disease-modifying agents” could potentially slow the progression of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal. Secondly, the focused design of multitargeted drugs acting on multiple key molecular pathways. Finally, the repositioning of drugs that are already available on the market for the novel (anti-AD) application provides a promising strategy for finishing clinical trials and re-marketing.

Figure 1. Distribution of clinical trials by phases (based on data available at the end of 2017 in the Thomson Reuters «Integrity» database, www.clinicaltrials.gov and Alzforum.org websites). The roman numbers indicate corresponding clinical trial phase, the Arabic number corresponds to the actual number of compounds in trials with the corresponding percentage in brackets.

Figure 2. Distribution of drug mode of action by phases (based on data available at the end of 2017 in the Thomson Reuters «Integrity» database, www.clinicaltrials.gov and Alzforum.org websites). Due to multitarget action of some compounds, they can be included in more than one group.

Figure 3. A schematic representation of beta-amyloid pathway that leads to AD pathology. The cleavage of APP of β-secretase and subsequently by
γ-secretase results in the production of an amyloid plaque. The nonpathogenic (nonamyloidogenic pathway) is initiated by α-secretase releasing sAPPα into the intracellular space. The resulting CTF-α fragment is cleaved by γ-secretase in the intermembrane space resulting in both the AICD and p3 fragments that are both non-plaque forming elements. The pathogenic (amyloidogenic pathway) initiated by β-secretase and resulted in sAPP-β release externally. The remaining CTF-β fragment is cleaved by γ-secretase and releases Aβ38-42 amino acid amyloid monomers. The externally released Aβ fragment forms toxic oligomers and eventually packaged in amyloid plaques.

Figure 4. Available structures for low-molecular-weight drugs affecting beta-amyloid proces.

Figure 5. A schematic representation of Tau deregulation resulting in AD pathology. Under normal conditions, Tau stabilizes microtubules within neurons. Microtubules are essential for normal axonal transport. In AD and other tauopathies kinases hyperphosphorylate Tau impairing its normal functioning and reducing the Tau binding to microtubules thus followed by subsequent sequestering of hyperphosphorylated Tau into neurofibrillary tangles (NFTs). The reduction of available of Tau leads to microtubule instability and reduces cellular transport further attributing to neuropathology.

Figure 6. Available structures of drugs affecting Tau aggregation.

Figure 7. Available structures of drugs affecting CNS receptors.

Figure 8. Available structures of inhibitors of enzymes involved in neuronal signal transduction.

Figure 9. Available structures of other drugs including antioxidants and compounds with undisclosed targets or mechanisms of action.

Figure 10. Drugs approved for treatment of Alzheimer’s disease.

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Table 1. Agents in phase I clinical trials for AD treatments.

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Table 2. Agents in phase II clinical trials for AD treatments.

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Table 3. Agents in phase III clinical trials for AD treatments.

ACKNOWLEDGEMENTS

The study was conducted in accordance to the Research Topic No. 48.8 «The search and determination of the mechanisms of neuroprotectors and stimulators of cognitive functions in the framework of the State Task of the Institute of Physiologically Active Compounds of the Russian Academy of Sciences (Topic: No: 0090-2017-0019).

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