Synthesis and Na(+)/H(+) exchanger-1 inhibitory activity of substituted (quinolinecarbonyl)guanidine derivatives.
The Na(+)/H(+) exchanger (NHE) is a protein expressed in many mammalian cell types. It is involved in intracellular pH (pH(i)) homeostasis by exchanging extracellular Na(+) for intracellular H(+). To date, nine NHE isoforms (NHE1-NHE9) have been identified. NHE1 is the most predominant isoform expressed in mammalian cardiac muscle. A novel series of substituted (quinolinecarbonyl)guanidine derivatives were designed and synthesized as NHE inhibitors. Most compounds can inhibit NHE1-mediated platelet swelling in a concentration-dependent manner, among which compound 7f was the most active and more potent than cariporide. Furthermore, compound 7f has also been demonstrated to exhibit the in vivo cardioprotective effects against SD rat myocardial ischemic-reperfusion injury superior to those of cariporide.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Dan
D
Mao
Yungen
Y
Xu
Xiaoping
X
Hu
Guomin
G
Zhang
Jin
J
Dong
Guoqing
G
Gong
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology
D002316:Cardiotonic Agents; D006146:Guanidines; D011804:Quinolines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide