Discovery of 2-[4-{{2-(2S,5R)-2-Cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic Acid (ABT-279): A Very Potent, Selective, Effective, and W

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• 作者：David J. Madar ; Hana Kopecka ; Daisy Pireh ; Hong Yong ; Zhonghua Pei ; Xiaofeng Li ; Paul E. Wiedeman ; Stevan W. Djuric ; Thomas W. Von Geldern ; Michael G. Fickes ; Lakshmi Bhagavatula ; Todd McDermott ; Stev
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：October 19, 2006
• 年：2006
• 卷：49
• 期：21
• 页码：6416 - 6420
• 全文大小：216K
• 年卷期：v.49,no.21(October 19, 2006)
• ISSN：1520-4804

文摘

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment oftype 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolididewarhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9.Further modification led to an extremely potent (Ki_DPP-IV = 1.0 nM) and selective (Ki_DPP8 > 30 M; Ki_DPP9> 30 M) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinicalsafety studies.