title: (5-Arylfuran-2-ylcarbonyl)guanidines as cardioprotectives through the inhibition of Na+/H+ exchanger isoform-1.
abstract: A series of (5-arylfuran-2-ylcarbonyl)guanidines was synthesized and evaluated for the NHE-1 inhibitory activity and cardiprotective efficacy against ischemia-reperfusion injury. Starting with (5-phenylfuran-2-ylcarbonyl)guanidine 47 with a moderate inhibitory effect on NHE-1, the compounds with various substituents at the phenyl ring were investigated with the aim to optimize the potency. In this study, the 2,5-disubstituted compounds appeared to have better activities than the other analogues, and the 2-methoxy-5-chlorophenyl compound 85 was found as a potent inhibitor of NHE-1 (IC(50) = 0.081 microM). Furthermore, 85 showed a marked reduction of infarct size in the rat myocardial infarction model in vivo and significant improvement of cardiac contractile function in the isolated rat heart ischemia model in vitro.
authors.affiliation: Medicinal Science Division, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 305-600, Korea.
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Sun Kyung
authors.initials: SK
authors.lastname: Hwang
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Lee
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D051381:Rats; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D002316:Cardiotonic Agents; D027682:Cation Transport Proteins; D005663:Furans; D006146:Guanidines; D008565:Membrane Proteins; D020033:Protein Isoforms; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; C502305:(5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl)guanidine