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((4R,5S)-5-氨基-4-(2,4,5-三氟苯基)环己-1-烯基)-(3-(三氟甲基)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)甲酮(ABT-341)的发现，一种用于治疗2型糖尿病的高效、选择性、口服有效且安全的二肽基肽酶IV抑制剂。

Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

作者信息

Pei Zhonghua, Li Xiaofeng, von Geldern Thomas W, Madar David J, Longenecker Kenton, Yong Hong, Lubben Thomas H, Stewart Kent D, Zinker Bradley A, Backes Bradley J, Judd Andrew S, Mulhern Mathew, Ballaron Stephen J, Stashko Michael A, Mika Amanda K, Beno David W A, Reinhart Glenn A, Fryer Ryan M, Preusser Lee C, Kempf-Grote Anita J, Sham Hing L, Trevillyan James M

机构信息

Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA.

出版信息

J Med Chem. 2006 Nov 2;49(22):6439-42. doi: 10.1021/jm060955d.

DOI:10.1021/jm060955d
PMID:17064063
Abstract

Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.

摘要

二肽基肽酶IV（DPP4）可使诸如胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）等葡萄糖调节激素失活，因此，抑制DPP4已成为治疗2型糖尿病的有效疗法。对高通量筛选先导化合物6进行优化后发现了25（ABT-341），这是一种高效、选择性且口服生物利用度高的DPP4抑制剂。口服给药时，25能使ZDF大鼠的血糖波动呈剂量依赖性降低。酰胺25在一系列体外和体内试验中均安全，可能代表一种治疗2型糖尿病的新型治疗药物。

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