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

Karnail S Atwal; Steven V O'Neil; Saleem Ahmad; Lidia Doweyko; Mark Kirby; Charles R Dorso; Gamini Chandrasena; Bang-Chi Chen; Rulin Zhao; Robert Zahler

doi:10.1016/j.bmcl.2006.06.077

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

Bioorg Med Chem Lett. 2006 Sep 15;16(18):4796-9. doi: 10.1016/j.bmcl.2006.06.077. Epub 2006 Jul 25.

Authors

Karnail S Atwal¹, Steven V O'Neil, Saleem Ahmad, Lidia Doweyko, Mark Kirby, Charles R Dorso, Gamini Chandrasena, Bang-Chi Chen, Rulin Zhao, Robert Zahler

Affiliation

¹ Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-5400, USA.

PMID: 16870436
DOI: 10.1016/j.bmcl.2006.06.077

Abstract

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 microM) 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.

MeSH terms

Administration, Oral
Animals
Biological Availability
Inhibitory Concentration 50
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry*
Piperidines / pharmacokinetics
Piperidines / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Rats
Sodium-Hydrogen Exchangers / antagonists & inhibitors*
Sodium-Hydrogen Exchangers / metabolism
Structure-Activity Relationship

Substances

Piperidines
Pyrimidines
Sodium-Hydrogen Exchangers