title: Zoniporide: a potent and highly selective inhibitor of human Na(+)/H(+) exchanger-1.
abstract: We evaluated the in vitro pharmacological profile of a novel, potent and highly selective Na(+)/H(+) exchanger-1 (NHE-1) inhibitor, [1-(Quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine hydrochloride monohydrate (zoniporide or CP-597,396). The potency and selectivity of zoniporide were determined via inhibition of 22Na(+) uptake by PS-120 fibroblast cell lines overexpressing human NHE-1, -2 or rat NHE-3. Additionally, potency for endogenous NHE-1 was confirmed via ex vivo human platelet swelling assay (PSA), in which platelet swelling was induced by exposure to sodium propionate. The pharmacological profile of zoniporide was compared with that of eniporide and cariporide. Zoniporide inhibited 22Na(+) uptake in fibroblasts expressing human NHE-1 in a concentration-dependent manner (IC(50) = 14 nM) and was highly selective (157-fold and 15,700-fold vs. human NHE-2 and rat NHE-3, respectively). Zoniporide was 1.64- to 2.6-fold more potent at human NHE-1 than either eniporide or cariporide (IC(50) = 23 and 36 nM, respectively). Zoniporide was also more selective at inhibiting human NHE-1 vs. human NHE-2 than either eniporide or cariporide (157-fold selective compared with 27- and 49-fold, respectively). All three compounds inhibited human platelet swelling with IC(50) values in low nanomolar range. From these results, we conclude that zoniporide represents a novel, potent and highly selective NHE-1 inhibitor.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases, MS: 8220-3118, Pfizer Global Research and Development, Pfizer Inc, Eastern Point Road, Groton, CT 06340, USA. ravi_b_marala@groton.pfizer.com
authors.forename: Ravi B
authors.initials: RB
authors.lastname: Marala
authors.forename: Janice A
authors.initials: JA
authors.lastname: Brown
authors.forename: Jimmy X
authors.initials: JX
authors.lastname: Kong
authors.forename: W Ross
authors.initials: WR
authors.lastname: Tracey
authors.forename: Delvin R
authors.initials: DR
authors.lastname: Knight
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Wester
authors.forename: Dexue
authors.initials: D
authors.lastname: Sun
authors.forename: Scott P
authors.initials: SP
authors.lastname: Kennedy
authors.forename: Ernest S
authors.initials: ES
authors.lastname: Hamanaka
authors.forename: Roger B
authors.initials: RB
authors.lastname: Ruggeri
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hill
mesh_terms: D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology
chemical_list: D006146:Guanidines; D011720:Pyrazoles; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; C093373:cariporide; C118397:eniporide; C424422:zoniporide; D012964:Sodium