title: Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1.
abstract: A novel series of arylcyclopropanecarboxyl guanidines was synthesized and evaluated for activity against the sodium hydrogen exchanger isoform-1 (NHE-1). In biological assays conducted in an AP1 cell line expressing the human NHE-1 isoform, the starting cyclopropane 3a (IC(50) = 3.5 microM) shows inhibitory activity comparable to cariporide (IC(50) = 3.4 microM). Structure-activity relationships are used to optimize the affinity of various acyl guanidines for NHE-1 by screening the effect of substituents at both aryl and cyclopropyl rings. It is demonstrated that introduction of appropriate hydrophobic groups at the phenyl ring and a gem-dimethyl group at the cyclopropane ring enhances the NHE-1 inhibitory activity by up to 3 orders of magnitude (compound 7f, IC(50) = 0.003 microM). In addition, the gem-dimethyl series of analogues seem to display improved oral bioavailability and longer plasma half-life in rats. Furthermore, the lead benzodihydrofuranyl analogue 1 (BMS-284640) shows over 380-fold increased NHE-1 inhibitory activity as well as improved selectivity for NHE-1 over NHE-2 compared to cariporide.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543, USA. saleem.ahmad@bms.com
authors.forename: S
authors.initials: S
authors.lastname: Ahmad
authors.forename: L M
authors.initials: LM
authors.lastname: Doweyko
authors.forename: S
authors.initials: S
authors.lastname: Dugar
authors.forename: N
authors.initials: N
authors.lastname: Grazier
authors.forename: K
authors.initials: K
authors.lastname: Ngu
authors.forename: S C
authors.initials: SC
authors.lastname: Wu
authors.forename: K J
authors.initials: KJ
authors.lastname: Yost
authors.forename: B C
authors.initials: BC
authors.lastname: Chen
authors.forename: J Z
authors.initials: JZ
authors.lastname: Gougoutas
authors.forename: J D
authors.initials: JD
authors.lastname: DiMarco
authors.forename: S J
authors.initials: SJ
authors.lastname: Lan
authors.forename: B J
authors.initials: BJ
authors.lastname: Gavin
authors.forename: A Y
authors.initials: AY
authors.lastname: Chen
authors.forename: C R
authors.initials: CR
authors.lastname: Dorso
authors.forename: R
authors.initials: R
authors.lastname: Serafino
authors.forename: M
authors.initials: M
authors.lastname: Kirby
authors.forename: K S
authors.initials: KS
authors.lastname: Atwal
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D027682:Cation Transport Proteins; D002460:Cell Line; D006224:Cricetinae; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D051381:Rats; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C437310:BMS 284604; D027682:Cation Transport Proteins; D003521:Cyclopropanes; D006146:Guanidines; D008565:Membrane Proteins; D020033:Protein Isoforms; C490998:SLC9A1 protein, human; C081517:SLC9A2 protein, human; C513110:Slc9a2 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers