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.
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.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-5400, USA.
authors.forename: Karnail S
authors.initials: KS
authors.lastname: Atwal
authors.forename: Steven V
authors.initials: SV
authors.lastname: O'Neil
authors.forename: Saleem
authors.initials: S
authors.lastname: Ahmad
authors.forename: Lidia
authors.initials: L
authors.lastname: Doweyko
authors.forename: Mark
authors.initials: M
authors.lastname: Kirby
authors.forename: Charles R
authors.initials: CR
authors.lastname: Dorso
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
authors.forename: Bang-Chi
authors.initials: BC
authors.lastname: Chen
authors.forename: Rulin
authors.initials: R
authors.lastname: Zhao
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D011743:Pyrimidines; D017923:Sodium-Hydrogen Exchangers