KCS

From our efforts to find a novel NHE-1 inhibitor based on bicyclic template, we found that (benzo[b]thiophene-2-carbonyl)guanidines with 4-substituent including halogen, nitrile, nitro, alkyl, and aryl groups showed good NHE-1 inhibitiory activity which was well translated into the cardioprotective efficacy. Especially the 4-cyano compound (KR-33028) excellently improved cardiac function in isolated rat heart ischemia model, and markedly reduced infarct size in the in vivo rat myocardial infarction model as well as strong inhibition on NHE-1. The nitrile function was introduced by microwave-promoted nucleophilic substitution using CuCN in DMF from 4-bromobenzothiophene-2-carboxylic ester in 20 minutes. The final acylguanidine was prepared by treating the ester with excess guanidine in DMF, purified by crystallization as a methanesulfonic acid salt.