Structure‐Activity relationship of Substituted 3‐Carbamyl‐4‐Methylpyrroles As Potential Antihypertensive Agents

3‐carbamyl‐4‐methyl pyrroles have promising antihypertensive and cardiac protective activity. This study was designed to identify more potent structures with wider therapeutic index. The structures of the 20 products were determined by NMR and mass spectrum. The analogs were tested for decreasing blood pressure and heart rate in rats and their efficacy and potency were compared. We found that 3‐carbamyl‐4‐methylpyrrole, MS23 [2‐[2‐(N‐ethyl‐N‐n‐propyl) amino] propionamido‐3‐carbamyl‐4‐methyl‐5‐(methylthioethyl) pyrrole] and MNP001 [2‐(2‐Piperidinopropionamido)‐3‐carbamyl‐4‐methyl‐5‐n‐butylpyrrole] were the most active structures. Both MS23 and MNP001 carry two pharmacophores for antagonizing L‐type calcium channels and inhibiting phosphodiesterases simultaneously. The replaced sulfur appeared to be the most sensitive site for oxidation and inactivation in vivo , on the grounds that co‐incubation of MS23 with H 2 O 2 caused rapid oxidation and inactivation of the sulfur compound. The increased lipophilicity due to the butyl tail of MNP001 may increase its ability to permeate the cytoplasmic membrane, therefore, its bioavailability and retention at the target sites.