Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV

Zhiyuan Zhang; Michael B Wallace; Jun Feng; Jeffrey A Stafford; Robert J Skene; Lihong Shi; Bumsup Lee; Kathleen Aertgeerts; Andy Jennings; Rongda Xu; Daniel B Kassel; Stephen W Kaldor; Marc Navre; David R Webb; Stephen L Gwaltney

doi:10.1021/jm101016w

Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV

J Med Chem. 2011 Jan 27;54(2):510-24. doi: 10.1021/jm101016w. Epub 2010 Dec 27.

Authors

Zhiyuan Zhang¹, Michael B Wallace, Jun Feng, Jeffrey A Stafford, Robert J Skene, Lihong Shi, Bumsup Lee, Kathleen Aertgeerts, Andy Jennings, Rongda Xu, Daniel B Kassel, Stephen W Kaldor, Marc Navre, David R Webb, Stephen L Gwaltney

Affiliation

¹ Takeda San Diego, Inc., 10410 Science Center Drive, San Diego, California 92121, United States.

PMID: 21186796
DOI: 10.1021/jm101016w

Abstract

The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Binding Sites
Biological Availability
Crystallography, X-Ray
Cytochrome P-450 Enzyme Inhibitors
Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
Dipeptidyl-Peptidase IV Inhibitors / chemistry
Dipeptidyl-Peptidase IV Inhibitors / pharmacology
Dogs
Macaca fascicularis
Models, Molecular
Pyrimidinones / chemical synthesis*
Pyrimidinones / chemistry
Pyrimidinones / pharmacology
Rats
Stereoisomerism
Structure-Activity Relationship

Substances

Cytochrome P-450 Enzyme Inhibitors
Dipeptidyl-Peptidase IV Inhibitors
Pyrimidinones