Anti-Alzheimer’s Disease Agents
From Antidepressants and/or Monoamine Oxidase Inhibitors towards Anti-Alzheimer’s Disease Agents
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
- CHE-SYN/Basic and Synthetic Chemistry/Chemistry
3 Approved without Funding
INEOS (Organo-Element Compounds), Russia, Moscow
- State Zakusov Institute of Pharmacology, Russia, Moscow\nInstitute of Higher Nervous Activity and Neurophysiology, Russia, Moscow
- Harvard Medical School / Harvard Center for Neurodegeneration & Repair, USA, MA, Cambridge
Project summarySince exact cause of Alzheimer’s disease (AD) is not known so far, the invention of “the magic bullet” for combating against this and related diseases is impeded. The goal of our study is the development of original medications for the treatment of dementia, or dementia–related diseases with depressive, psychotic, aggressive and/or amnestic syndromes including AD in different stages as well as mild cognitive impairment (MCI). Our primary focus is search for new agents that may at least be useful for patients with MCI, and this will be a spur to the development of more effective drugs for the therapy of dementia in the future. Design of the novel compounds will be conducted using our experience in the development of medications for treatment of neurological and psychiatric disorders gained during work under CRDF RB 2032, INTAS-99-0433 and 00-711 as well Russian grants.
Monoamine oxidase (MAO) inhibitors have well documented efficacy in treating depression-related disorders and pathologic anger as well aggression. However, recently studies suggest that MAO inhibitors are promising as potential neuroprotectors and drugs for treatment of neurodegenerative diseases including Parkison’s and Alzheimer’s diseases. One of the aims of the present study is to evaluate the possibility of separating neuroprotective and MAO inhibiting properties among synthesized by us heterocycles with high MAO inhibitory activity. Divergence of neuroprotective and MAO inhibitory effects was shown to be achieved with rasagiline and its neuroprotective S-isomer, TVP1022. The latter being more than three orders of magnitude less potent MAO inhibitor than the former. Rasagiline has been chosen by the National Institutes of Health (NIH) for the study of its neuroprotective effects in neurodegenerative diseases.
Prof. Velezheva is Head of Laboratory for Synthesis of the Biologically Active Heterocyclic Compounds, INEOS RAS. Her team has experience in the development of the novel organic reactions and synthetic methods applicable in drug-design and these will be used in the project. The design of de novo structures will be carried out by association of structural fragments of different drugs and/or lead compounds in the same molecule. Indole derivatives, fused indole, and/or 4-quinolone and/or dihydropyrrole ones will be used as starting compounds. The objectives would be achieved by alteration of both heterocyclic core of parent structures and its substituents. Drug prototypes are chosen taking the heterocyclic core of antidepressants and/or MAO inhibitors such as pyrazidole, tetrindol and pipofezinum (drugs employed clinically in Russia) as a base. Experimental drugs rasagiline, TV3326, rolipram, CX-546, LY4041187 and LY503430 etc. will be considered by the choice of pharmacophoric groups for compounds designed. Our new synthetic methods and reactions will be used in the framework of this project as it was done during the above CRDF grant period when anti-tuberculosis lead compounds were developed by us in collaboration with Dr. P.J. Brennan from Colorado State University (CSU). Then a series of compounds with dual inhibitory activity against M. tuberculosis and monoamine oxidase was synthesized and selected for the further assays. The leader, GS65, was selected from ca.100 compounds synthesized and tested using in vitro models. Recently GS65 was being tested in a mouse model for in vivo inhibition of M. tuberculosis growth. A patent based on a new synthetic method and anti-TB activity of GS65 and its analogs is being pursued by CSU on behalf of INEOS and CSU. It should be noted that the first MAO inhibitor and central nervous stimulant, iproniazid, was initially found as an antituberculosis drug. The continuation of the studies on MAO inhibitors may lead to the elaboration of new drugs with new profiles of biological activity.
The investigation of neuroprotective potential of novel compounds synthesized will be one of the major goals of Prof. Gulyaeva’s team (Head of Department of Functional Biochemistry of the Nervous System, IHNA RAS). The main approach the team will use is identification of novel mechanism-based drugs via their interaction with specific biological targets (neurotransmitter system receptors, redox enzymes, nitrergic system) will be carried out. Besides the experience in in vitro studies, the members of the team are experts in modeling a variety of neurological diseases in rodents (including stroke, epilepsy, Parkinson’s disease and AD) with the study of behavior/learning/memory, neurological deficit and brain pathomorphology. As a result of this team’s work, neuroprotective properties targeted at selected stages of the pathoneurochemical cascade in a brain will be revealed for compounds under study. The field of neurochemical expertise of the team includes: free radical-mediated processes and antioxidants; the nitrergic system and nitric oxide synthase isoforms; caspases, calpains and other “apoptotic” enzymes activities.
At last, Prof. Voronina’s team (Head of Psychopharmacology Lab, Institute of Pharmacology RAMS) would search for lead structures among the compounds synthesized in relation to their pharmacological activities including cognitive enhancing and antidepressant properties. The members of the team are experts in development of novel psychotropic and neurological drugs (including cognitive enhancers, antidepressants, antihypoxants, anxiolytics, anticonvulsants, antipsychotics, antiparkinsonians) on the basis of structure-activity relationships, as well as in studying of mechanisms of novel drugs action.
Collaborator of the project is Dr. G. D. Cuny, Director of Medicinal Chemistry Laboratory for Drug Discovery in the Neurodegeneration Brigham & Women’s Hospital and Harvard Medical School, famous scientist, author of a number publications in the area of neurodegeneration. Foreign collaborator will:
- Provide screening of the compounds synthesized in many types of biological assays related to neurodegeneration.
- Give help in getting information, useful for carrying out the project. Participate in joint discussion of project results and in publishing joint articles and report thesis.
In a long-term outlook, the development of effective anti-AD drugs with different ratio of “non-specific” general neuroprotective and “specific” anti-AD can be achieved. Since AD includes a large variety of forms and disease courses, this approach may establish a future trend to a pathogenetically directed drug design with the desired combination and ratios of activities appropriate for the treatment of specific forms of AD.
This project will contribute to further development of the theoretical basis for the involvement of cerebral enzyme systems and neurotransmitter systems in both the disturbances of the central nervous system and neuroprotective mechanisms.
The project meets all the ISTC requirements because:
- It promotes the integration of scientists from Russia into the international science community, since the part of research will be carried out together with the foreign scientists, experts in medicinal chemistry, biochemistry and pharmacology. There is a lot of experience in team-work between the participants of this project and their foreign colleagues (Velezheva V. S. et al. Novel Pyridazino[4,3-b]indoles with Dual Inhibitory Activity Against Mycobacterium tuberculosis and Monoamine Oxidase. J. Med. Chem. 2004, 47, 3455-3461. Onufriev MV, Gulyaeva NV, Terenina NB, Tolstenkov OO, Gustafsson MK. The effect of a nitric oxide donor on the synthesis of cGMP in Hymenolepisdiminuta: a radiometric study. Parasitol Res. 2005, 95, 22-24. Gulyaeva N. et al. Tongue protrusion: a simple test for neurological recovery in rats following focal cerebral ischemia. J Neurosci. Methods. 2003, 125, 183-93.
- It supports fundamental researches in the study of neurodegenerative disorders, since developing respective approaches will allow creating drugs with low toxicity, effective at minimal doses and suitable for application in medicine. It promotes the solution of national and international problems of public health services, since new medications can be applied both in Russia and in other countries.
- It favors the solution of local and international problems in the field of the public health service since created novel drugs will be suitable for application in the medical practice as in Russia so abroad.
- It favors the transfer to the market economy since the development of new drugs can be realized by enterprises of different property forms.
- The main part of team comes from the military branch of the economy.
Design concept will originate from recognition of specific targets typical for different classes compounds synthesized. A development of novel mechanism-based agents with neuroprotective and/or anti-depressant properties to be fulfilled under the project period and initiated to pre-clinical trials.