Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine (23)

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• 作者：Tesfaye Biftu ; Xiaoxia Qian ; Ping Chen ; Dennis Feng ; Giovanna Scapin ; Ying-Duo Gao ; Jason Cox ; Ranabir Sinha Roy ; George Eiermann ; Huabing He ; Kathy Lyons ; Gino Salituro ; Sangita Patel ; Alex ; er Petrov ; Feng Xu ; Shiyao Sherrie Xu ; Bei Zhang ; Charles Caldwell ; Joseph K. Wu ; Kathy Lyons ; et al.
• 关键词：DPP-IV ; Tetrahydropyran ; DPP-4 inhibitors ; Diabetes
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 October, 2013
• 年：2013
• 卷：23
• 期：19
• 页码：5361-5366
• 全文大小：2312 K

文摘

A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.