Discovery of non-covalent dipeptidyl peptidase IV inhibitors which induce a conformational change in the active site

被引：18

作者：

Sheehan, Scott M. ^{[1
]}

Mest, Hans-Juergen

Watson, Brian M.

Klimkowski, Valentine J.

Timm, David E.

Cauvin, Annick

Parsons, Stephen H.

Shi, Qing

Canada, Emily J.

Wiley, Michael R.

Ruehter, Gerd

Evers, Britta

Petersen, Soenke

Blaszczak, Larry C.

Pulley, Shon R.

Margolis, Brandon J.

Wishart, Graham N.

Renson, Beatrice

Hankotius, Dirk

Mohr, Michael

Zechel, Johann-Christian

Kalbfleisch, J. Michael

Dingess-Hammond, Elizabeth A.

Boelke, Andre

Weichert, Andreas G.

机构：

[1] Lilly Res Labs, Indianapolis, IN 46285 USA

[2] Lilly Forsch GmbH, D-22419 Hamburg, Germany

[3] Lilly Dev Ctr, B-1348 Louvain, Belgium

[4] Eli Lilly & Co, Lilly Res Ctr, Windlesham GU20 6PH, Surrey, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 06期

关键词：

dipeptidyl peptidase IV; protease inhibitor; X-ray co-crystal structure; oral glucose tolerance test;

D O I：

10.1016/j.bmcl.2006.12.074

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

A series of non-covalent inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV) were found to adopt a U-shaped binding conformation in X-ray co-crystallization studies. Remarkably, Tyr547 undergoes a 70 degrees side-chain rotation to accommodate the inhibitor and allows access to a previously unexposed area of the protein backbone for hydrogen bonding. (c) 2007 Elsevier Ltd. All rights reserved.

引用

页码：1765 / 1768

页数：4

共 19 条

[1]

Abbenante Giovanni, 2005, Med Chem, V1, P71, DOI 10.2174/1573406053402569

[2]

Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of Type 2 diabetes [J].