Synthesis of (aryloxy)alkylamines. 2. Novel imidazo-fused heterocycles with calcium channel blocking and local anesthetic activity

• Published in: Journal of medicinal chemistry Vol. 31; no. 11; pp. 2221 - 2227
• Main Authors: Sanfilippo, Pauline J, Urbanski, Maud, Press, Jeffery B, Dubinsky, Barry, Moore, John B
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-11-1988
• Subjects: Amines - chemical synthesis; Amines - pharmacology; Anesthetics, Local - chemical synthesis; Anesthetics, Local - pharmacology; Animals; calcium; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - pharmacology; cardiac muscle; Drug Evaluation, Preclinical; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - pharmacology; Imidazoles - chemical synthesis; Imidazoles - pharmacology; In Vitro Techniques; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Myocardial Contraction - drug effects; Rabbits; smooth muscle; Trachea - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00119a026

A series of imidazo-fused heterocycles substituted with an aryloxy)alkylamine side chain were prepared as modifications to butoprozine (I) and found to possess calcium channel blocking activity similar in potency to that of bepridil in trachea smooth muscle and similar to that of verapamil in nitrendipine binding affinity in rabbit cardiac muscle. Of the various imidazo-fused heterocycles prepared, the imidazo[1,2-a]pyridines were also found to be potent local anesthetic agents. While most compounds in this series were equipotent to lidocaine in our initial screen, compounds 2 and 35 showed local anesthetic activity approximately 100 times more potent than lidocaine in our preliminary assays. These compounds represent a novel structural class of local anesthetic agents, and compound 2 is under further investigation.