7-Phenyl-imidazoquinolin-4(5H)-one derivatives as selective and orally available mPGES-1 inhibitors

被引：32

作者：

Shiro, Tomoya ^{[1
]}

Kakiguchi, Keisuke ^{[2
]}

Takahashi, Hirotada ^{[1
]}

Nagata, Hidetaka ^{[1
]}

Tobe, Masanori ^{[2
]}

机构：

[1] Dainippon Sumitomo Pharma Co Ltd, Drug Res Div, Konohana Ku, Osaka 5540022, Japan

[2] Dainippon Sumitomo Pharma Co Ltd, Drug Res Div, Suita, Osaka 5640053, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 11期

关键词：

mPGES-1; PGE(2); Imidazoquinolin-4(5H)-one; Oral absorption; PROSTAGLANDIN E-2 SYNTHASE; THERAPEUTIC TARGET; BIOLOGICAL EVALUATION; MICE LACKING; PAIN; BIOSYNTHESIS; INFLAMMATION; POTENT; SAR;

D O I：

10.1016/j.bmc.2013.03.069

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

To identify compounds with strong mPGES-1 inhibitory activity and clear in vitro ADME profile, we optimized the lead compound 1 by carrying our substitutions at the C(7)-and C(8)-positions. Replacement of the bromine atom of 1 with various substituents led to identification of the phenyl group as the best C(7)-substituent giving strong inhibitory activity with good in vitro ADME profile. Further SAR examination on both the C(2)-and the C(7)-phenyl groups provided compound 39 as the best candidate for further development. Compound 39 exhibited strong mPGES-1 inhibitory activity (IC50 = 4.1 nM), potent cell-based functional activity (IC50 = 33 nM) with good mPGES-1 selectivity (over 700-fold), excellent in vitro ADME profile, and good oral absorption in rat PK study. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：2868 / 2878

页数：11

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