The discovery of novel 5,6,5- and 5,5,6-tricyclic pyrrolidines as potent and selective DPP-4 inhibitors

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• 作者：Jason M. Cox^a ; ^{jason_cox@merck.com" class="auth_mail" title="E-mail the corresponding author} ; Hong D. Chu^a ; Jeffrey T. Kuethe^a ; Ying-Duo Gao^e ; Giovanna Scapin^e ; George Eiermann^b ; Huaibing He^d ; Xiaohua Li^d ; Kathryn A. Lyons^d ; Joseph Metzger^c ; Aleksandr Petrov^b ; Joseph K. Wu^c ; Shiyao Xu^d ; Ranabir Sinha-Roy^c ; Ann E. Weber^a ; Tesfaye Biftu^a
• 关键词：Dipeptidyl peptidase IV (DPP-4) ; Type 2 diabetes mellitus ; Sitagliptin ; Omarigliptin
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：26
• 期：11
• 页码：2622-2626
• 全文大小：1559 K

文摘

Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure–activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.