1-((3S,4S)-4-Amino-1-(4-substituted-1,3,5-triazin-2-yl) pyrrolidin-3-yl)-5, 5-difluoropiperidin-2-one inhibitors of DPP-4 for the treatment of type 2 diabetes

被引：15

作者：

Andrews, Kim M. ^{[1
]}

Beebe, David A. ^{[1
]}

Benbow, John W. ^{[1
]}

Boyer, David A. ^{[1
]}

Doran, Shawn D. ^{[1
]}

Hui, Yu ^{[1
]}

Liu, Shenping ^{[1
]}

McPherson, R. Kirk ^{[1
]}

Neagu, Constantin ^{[1
]}

Parker, Janice C. ^{[1
]}

Piotrowski, David W. ^{[1
]}

Schneider, Steven R. ^{[1
]}

Treadway, Judith L. ^{[1
]}

VanVolkenberg, Maria A. ^{[1
]}

Zembrowski, William J. ^{[1
]}

机构：

[1] Pfizer Inc, Global Res & Dev, Groton Labs, Groton, CT 06340 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 06期

关键词：

Type; 2; diabetes; Dipeptidyl peptidase; DPP-4; DIPEPTIDYL-PEPTIDASE-IV; VIVO TOXICOLOGICAL OUTCOMES; IN-VIVO; POTENT; DISCOVERY; DESIGN; DRUG; DERIVATIVES; PROGRESS;

D O I：

10.1016/j.bmcl.2011.01.055

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A 3-amino-4-substituted pyrrolidine series of dipeptidyl peptidase IV (DPP-4) inhibitors was rapidly developed into a candidate series by identification of a polar valerolactam replacement for the lipophilic 2,4,5-trifluorophenyl pharmacophore. The addition of a gem-difluoro substituent to the lactam improved overall DPP-4 inhibition and an efficient asymmetric route to 3,4-diaminopyrrolidines was developed. Advanced profiling of a subset of analogs identified 5o with an acceptable human DPP-4 inhibition profile based on a rat PK/PD model and a projected human dose that was suitable for clinical development. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：1810 / 1814

页数：5

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