Synthesis and biological activity of 5-aryl-4-(4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl)pyrimidine analogs as potent, highly selective, and orally bioavailable NHE-1 inhibitors

被引：35

作者：

Atwal, Karnail S.

O'Neil, Steven V.

Ahmad, Saleem

Doweyko, Lidia

Kirby, Mark

Dorso, Charles R.

Chandrasena, Gamini

Chen, Bang-Chi

Zhao, Rulin

Zahler, Robert

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Discovery Chem, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Cardiovasc Biol, Princeton, NJ 08543 USA

[3] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Drug Metab, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 18期

关键词：

NHE; NHE-1; sodium hydrogen exchanger; EXCHANGER; ISOFORM; TRIAL;

D O I：

10.1016/j.bmcl.2006.06.077

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of potent inhibitors of the sodium hydrogen exchanger-1 (NHE-1) is described. Structure-activity relationships identified the 3-methyl-4-fluoro analog 9t as a highly potent (IC50 = 0.0065 mu M) and selective (NHE-2/NHE-1 = 1400) non-acylguanidine NHE-1 inhibitor. Pharmacokinetic studies showed that compound 9t has an oral bioavailability of 52% and a plasma half life of 1.5 h in rats. Because of its promising potency, selectivity, and a good pharmacokinetic profile, compound 9t was selected for further studies. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：4796 / 4799

页数：4

共 10 条

[1] Aminoimidazoles as bioisosteres of acylguanidines: novel, potent, selective and orally bioavailable inhibitors of the sodium hydrogen exchanger isoform-1 [J].