苯并恶嗪酮类作为过氧化物酶体增殖物激活受体γ（PPARγ）激动剂。2. 酰胺取代基的构效关系及在2型糖尿病模型中的体内实验结果。

Benzoxazinones as PPARgamma agonists. 2. SAR of the amide substituent and in vivo results in a type 2 diabetes model.

作者信息

Rybczynski Philip J, Zeck Roxanne E, Dudash Joseph, Combs Donald W, Burris Thomas P, Yang Maria, Osborne Melville C, Chen Xiaoli, Demarest Keith T

机构信息

Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202, Raritan, New Jersey 08869, USA.

出版信息

J Med Chem. 2004 Jan 1;47(1):196-209. doi: 10.1021/jm0301888.

DOI:10.1021/jm0301888

PMID:14695833

Abstract

A series of benzoxazinones has been synthesized and tested for PPARgamma agonist activity. Synthetic approaches were developed to provide either racemic or chiral compounds. In vitro functional potency could be measured through induction of the aP2 gene, a target of PPARgamma. These studies revealed that compounds with large aliphatic chains at the nitrogen of the benzoxazinone were the most potent. Substitution of the chain was tolerated and in many cases enhanced the in vitro potency of the compound. Select compounds were further tested for metabolic stability, oral bioavailability in rats, and efficacy in db/db mice after 11 days of dosing. In vivo analysis with 13 and 57 demonstrated that the series has potential for the treatment of type 2 diabetes.

摘要

已合成了一系列苯并恶嗪酮并测试其过氧化物酶体增殖物激活受体γ（PPARγ）激动剂活性。开发了合成方法以提供外消旋或手性化合物。可以通过诱导PPARγ的靶标aP2基因来测量体外功能效力。这些研究表明，在苯并恶嗪酮的氮原子处具有大脂肪族链的化合物效力最强。该链的取代是可接受的，并且在许多情况下提高了化合物的体外效力。选择的化合物进一步测试了代谢稳定性、在大鼠中的口服生物利用度以及给药11天后在db/db小鼠中的疗效。用13和57进行的体内分析表明该系列具有治疗2型糖尿病的潜力。