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P1‐090: DISCOVERY OF NOVEL SMALL MOLECULES FOR THE TREATMENT OF ALZHEIMER'S DISEASE
Author(s) -
Murumkar Prashant R.,
Yadav Mange Ram,
Darreh-Shori Taher,
Kumar Amit,
Kumar Rajnish
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.645
Subject(s) - chemistry , dtnb , in vitro , absorbance , chromatography , aché , acetylcholinesterase , phosphate buffered saline , enzyme , in vivo , ic50 , biochemistry , glutathione , biology , microbiology and biotechnology
Background: SUVN-502 is a pure 5-HT6 receptor antagonist being developed for the symptomatic treatment of Alzheimer’s disease (AD). It has excellent ADME properties and robust efficacy in preclinical cognition models. SUVN-502 exhibited procognitive effects and modulated acetylcholine levels in brain regions relevant for cognition when administered alone. SUVN-502 has excellent margin of safety in long-term preclinical safety evaluation. In healthy human subjects, SUVN-502 was well tolerated following single or multiple oral administrations. SUVN-502 is being evaluated in a phase 2a multicenter, randomized, double-blind, parallel group, 26-week, placebo-controlled study. This study is regulated by US FDA. A total of 563 subjects with moderate Alzheimer’s disease receiving stable doses of donepezil HCl and memantine HCl have been recruited. Randomized subjects received either placebo or SUVN-502 (50 or 100 mg) on top of stable doses of donepezil and memantine for 26 weeks. Methods: The effect of SUVN-502 + donepezil + memantine combination was evaluated in animal models for procognitive property (Morris water maze task), acetylcholine modulation (microdialysis) and theta modulation (electrophysiology). The pharmacokinetic interaction of the SUVN-502, donepezil and memantine was also studied in a satellite group of rats. Results: Co-treatment of SUVN-502 with donepezil and memantine significantly potentiated the procognitive effects when compared with memantine and donepezil treatment alone in the Morris water maze task. SUVN-502 also potentiated the effects of donepezil and memantine combination in hippocampal acetylcholine levels and brain oscillatory activity. There were no significant changes in the exposures of SUVN-502 or donepezil or memantine. Conclusions: SUVN-502 + Donepezil + Memantine represent a first in class promising new approach for the symptomatic treatment of Alzheimer’s disease. These preclinical results provide the strong rational for the design of currently ongoing SUVN-502 clinical study.