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ID: ALA1149356

Journal: Bioorg Med Chem Lett

Title: 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.

Authors: Atwal KS, O'Neil SV, Ahmad S, Doweyko L, Kirby M, Dorso CR, Chandrasena G, Chen BC, Zhao R, Zahler R.

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.

CiteXplore: 16870436

DOI: 10.1016/j.bmcl.2006.06.077