Design, synthesis and biological evaluation of novel substituted benzoylguanidine derivatives as potent Na+/H+ exchanger inhibitors.
A novel series of substituted benzoylguanidine derivatives were designed and synthesized as potent NHE1 inhibitors. Most compounds can significantly inhibit NHE1-mediated platelet swelling in a concentration-dependent manner, among which compound 5f (IC(50)=3.60 nM) and 5l (IC(50)=4.48 nM) are 18 and 14 times respectively more potent than cariporide (IC(50)=65.0 nM). Furthermore, when tested in vivo and in vitro, compound 5f showed superior cardioprotective effects against SD rat myocardial ischemic-reperfusion injury over cariporide, representing a promising lead compound for further exploration.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Wen-Ting
WT
Xu
Ning
N
Jin
Jing
J
Xu
Yun-Gen
YG
Xu
Qiu-Juan
QJ
Wang
Qi-Dong
QD
You
D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D017202:Myocardial Ischemia / Q000517:prevention & control; D051381:Rats; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*
D001565:Benzoates; D002316:Cardiotonic Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers