Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin inhibitors

被引：52

作者：

Powell, Noel A. ^{[1
]}

Ciske, Fred L. ^{[1
]}

Cai, Cuiman ^{[1
]}

Holsworth, Daniel D. ^{[1
]}

Mennen, Ken ^{[1
]}

Van Huis, Chad A. ^{[1
]}

Jalaie, Mehran ^{[1
]}

Day, Jacqueline ^{[1
]}

Mastronardi, Michelle ^{[1
]}

McConnell, Pat ^{[1
]}

Mochalkin, Igor ^{[1
]}

Zhang, Erli ^{[1
]}

Ryan, Michael J. ^{[1
]}

Bryant, John ^{[1
]}

Collard, Wendy ^{[1
]}

Ferreira, Suzie ^{[1
]}

Gu, Chungang ^{[1
]}

Collins, Roxane ^{[1
]}

Edmunds, Jeremy J. ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Michigan Labs, Ann Arbor, MI 48105 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2007年 / 15卷 / 17期

关键词：

hypertension; renin; structure-based drug design; oral; bioavailability;

D O I：

10.1016/j.bmc.2007.05.069

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：

We report the design and synthesis of a series of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin - 3 -ones as orally bioavailable small molecule inhibitors of renin. Compounds with a 2-methyl-2-aryl substitution pattern exhibit potent renin inhibition and good permeability, solubility, and metabolic stability. Oral bioavailability was found to be dependent on metabolic clearance and cellular permeability, and was optimized through modulation of the sidechain that binds in the S3(sp) subsite. (c) 2007 Elsevier Ltd. All rights reserved.

引用

页码：5912 / 5949

页数：38

共 54 条

[1]

*AM HEART ASS, 2006, HEART DIS STROK STAT

[2]

BAESCHLIN DK, Patent No. 2005051895

[3]

BALDWIN JJ, Patent No. 20060421250

[4]

BEZENCON O, Patent No. 2006059304

[5]

BEZENCON O, Patent No. 2003093267

[6]

BEZENCON O, Patent No. 2005040120

[7]

BEZENCON O, Patent No. 2006079988

[8]

Bittner B, 2002, ARZNEIMITTELFORSCH, V52, P593

[9]

BREITENSTEIN W, Patent No. 2006066896

[10]

BREITENSTEIN W, Patent No. 2006069788

← 1 2 3 4 5 6 →