Title of article :
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
Author/Authors :
Karnail S. Atwal، نويسنده , , Steven V. O’Neil، نويسنده , , Saleem Ahmad، نويسنده , , Lidia Doweyko، نويسنده , , Mark Kirby، نويسنده , , Charles R. Dorso، نويسنده , , Gamini Chandrasena، نويسنده , , Bang-Chi Chen، نويسنده , , Rulin Zhao، نويسنده , , Robert Zahler، نويسنده ,
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 μM) 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.
