title: Synthesis of novel ligustrazine derivatives as NA+/H+ exchange inhibitors.
abstract: A novel series of 3,5,6-trimethylpyrazine-2-methoxy (or methylamino) substituted benzoyl-guanidine derivatives were designed and synthesized as Na(+)/H(+) exchange (NHE) inhibitors. In this study, compounds with electron-withdrawing substituents on the benzene ring seemed to improve NHE-1 inhibitory activities. Compounds 6d, 6k, and 6l were found to be potent inhibitors of NHE-1 (IC(50)=3.0±1.6, 3.0±1.4, and 1.6±0.4 nmol/l, resp.). Furthermore, they showed a remarkable reduction of infarct size in the rat myocardial infarction model in vivo.
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Ren
authors.forename: Jin
authors.initials: J
authors.lastname: Dong
authors.forename: Yungen
authors.initials: Y
authors.lastname: Xu
authors.forename: Nan
authors.initials: N
authors.lastname: Wen
authors.forename: Guoqing
authors.initials: G
authors.lastname: Gong
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D009203:Myocardial Infarction / Q000188:drug therapy; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C556190:3-bromo-N-(diaminomethylidene)-4-(((3,5,6-trimethylpyrazin-2-yl)methyl)amino)benzamide hydrochloride; C556187:3-bromo-N-(diaminomethylidene)-4-((3,5,6-trimethylpyrazin-2-yl)methoxy)benzamide hydrochloride; D001549:Benzamides; D002316:Cardiotonic Agents; C556189:N-(diaminomethylidene)-3-nitro-4-(((3,5,6-trimethylpyrazin-2-yl)methyl)amino)benzamide hydrochloride; D011719:Pyrazines; D017923:Sodium-Hydrogen Exchangers; D003402:Creatine Kinase; C017953:tetramethylpyrazine