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2-[4-{{2-(2S,5R)-2-氰基-5-乙炔基-1-吡咯烷基]-2-氧代乙基]氨基]-4-甲基-1-哌啶基]-4-吡啶羧酸（ABT-279）的发现：一种非常强效、选择性高、有效且耐受性良好的二肽基肽酶-IV抑制剂，可用于治疗糖尿病。

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 well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.

作者信息

Madar David J, Kopecka Hana, Pireh Daisy, Yong Hong, Pei Zhonghua, Li Xiaofeng, Wiedeman Paul E, Djuric Stevan W, Von Geldern Thomas W, Fickes Michael G, Bhagavatula Lakshmi, McDermott Todd, Wittenberger Steven, Richards Steven J, Longenecker Kenton L, Stewart Kent D, Lubben Thomas H, Ballaron Stephen J, Stashko Michael A, Long Michelle A, Wells Heidi, Zinker Bradley A, Mika Amanda K, Beno David W A, Kempf-Grote Anita J, Polakowski James, Segreti Jason, Reinhart Glenn A, Fryer Ryan M, Sham Hing L, Trevillyan James M

机构信息

Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6001, USA.

出版信息

J Med Chem. 2006 Oct 19;49(21):6416-20. doi: 10.1021/jm060777o.

DOI:10.1021/jm060777o
PMID:17034148
Abstract

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead 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 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.

摘要

二肽基肽酶-IV（DPP-IV）抑制剂有望成为治疗2型糖尿病的下一类主要药物。对2-氰基吡咯烷弹头C5位取代基的构效关系研究，发现了对DPP-IV有强效抑制作用且对DPP8和DPP9无活性的抑制剂。进一步修饰得到了一种极具潜力（DPP-IV的Ki值为1.0 nM）且具有选择性（DPP8的Ki值>30 μM；DPP9的Ki值>30 μM）的临床候选药物ABT-279，该药物可口服，在临床前安全性研究中疗效显著且安全性极高。

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