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2021 - Discovery and Preclinical Characterization of Usmarapride (SUVN-D4010): A Potent, Selective 5-HT4 Receptor Partial Agonist for the Treatment of Cognitive Deficits Associated with Alzheimer’s Disease

icon pl  Patchliner Publication in Journal of Medicinal Chemistry (2021)

Nirogi R., Mohammed A. R., Shinde A. K., Gagginapally S. R., Kancharla D. M., Ravella S. R., Bogaraju N., Middekadi V. R., Subramanian R., Palacharla R. C., Benade V., Muddana N., Abraham R., Medapati R. B., Thentu J. B., Mekala V. R., Petlu S., Lingavarapu B. B., Yarra S., Kagita N., Goyal V. K., Pandey S. K., Jasti V.


Journal of Medicinal Chemistry (2021) doi:10.1021/acs.jmedchem.1c00703


A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment of cognitive deficits associated with Alzheimer’s disease. Starting from a reported 5-HT4R antagonist, a systematic structure–activity relationship was conducted, which led to the discovery of potent and selective 5-HT4R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced physicochemical–pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.

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