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)

被引：34

作者：

Biftu, Tesfaye ^{[1
]}

Qian, Xiaoxia ^{[1
]}

Chen, Ping ^{[1
]}

Feng, Dennis ^{[1
]}

Scapin, Giovanna ^{[1
]}

Gao, Ying-Duo ^{[1
]}

Cox, Jason ^{[1
]}

Roy, Ranabir Sinha ^{[1
]}

Eiermann, George ^{[1
]}

He, Huabing ^{[2
]}

Lyons, Kathy ^{[2
]}

Salituro, Gino ^{[2
]}

Patel, Sangita ^{[1
]}

Petrov, Alexander ^{[1
]}

Xu, Feng ^{[1
]}

Xu, Shiyao Sherrie ^{[2
]}

Zhang, Bei ^{[1
]}

Caldwell, Charles ^{[1
]}

Wu, Joseph K. ^{[1
]}

Lyons, Kathy ^{[2
]}

Weber, Ann E. ^{[1
]}

机构：

[1] Merck Res Labs, Rahway, NJ 07065 USA

[2] Merck Res Labs, PPDM Bioanalyt, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 19期

关键词：

DPP-IV; Tetrahydropyran; DPP-4; inhibitors; Diabetes; RATIONAL DESIGN; IDENTIFICATION; HOMOLOG; CLONING; POTENT;

D O I：

10.1016/j.bmcl.2013.07.061

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2013 Elsevier Ltd. All rights reserved.

引用

收藏

页码：5361 / 5366

页数：6

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