期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 15, 页码 10641-10665出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00703
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A novel 5-HT4R partial agonist was synthesized and demonstrated significant nonclinical cognitive efficacy, as well as potential disease-modifying properties. Phase 1 and Phase 2 clinical studies confirmed therapeutic effects of the drug with no major safety concerns for long-term use.
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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