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

Z Zhang, MB Wallace, J Feng, JA Stafford…

Index: Zhang, Zhiyuan; Wallace, Michael B.; Feng, Jun; Stafford, Jeffrey A.; Skene, Robert J.; Shi, Lihong; Lee, Bumsup; Aertgeerts, Kathleen; Jennings, Andy; Xu, Rongda; Kassel, Daniel B.; Kaldor, Stephen W.; Navre, Marc; Webb, David R.; Gwaltney, Stephen L. Journal of Medicinal Chemistry, 2011 , vol. 54, # 2 p. 510 - 524

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Citation Number: 48

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.