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

被引：17

作者：

Cox, Jason M. ^{[1
]}

Chu, Hong D. ^{[1
]}

Kuethe, Jeffrey T. ^{[1
]}

Gao, Ying-Duo ^{[5
]}

Scapin, Giovanna ^{[5
]}

Eiermann, George ^{[2
]}

He, Huaibing ^{[4
]}

Li, Xiaohua ^{[4
]}

Lyons, Kathryn A. ^{[4
]}

Metzger, Joseph ^{[3
]}

Petrov, Aleksandr ^{[2
]}

Wu, Joseph K. ^{[3
]}

Xu, Shiyao ^{[4
]}

Sinha-Roy, Ranabir ^{[3
]}

Weber, Ann E. ^{[1
]}

Biftu, Tesfaye ^{[1
]}

机构：

[1] Merck Res Labs, Dept Chem, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[2] Merck Res Labs, Dept Pharmacol Screening & Prot Sci, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[3] Merck Res Labs, Dept Cardiometab Dis, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[4] Merck Res Labs, Dept PPDM, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[5] Merck Res Labs, Dept Struct Chem, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 11期

关键词：

Dipeptidyl peptidase IV (DPP-4); Type 2 diabetes mellitus; Sitagliptin; Omarigliptin; RATIONAL DESIGN; PEPTIDASE; HOMOLOG; BIOLOGY; ANALOGS;

D O I：

10.1016/j.bmcl.2016.04.020

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：2622 / 2626

页数：5

共 22 条

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