Synthesis and cardiotonic activity of novel biimidazoles

• Published in: Journal of medicinal chemistry 1990-01, Vol.33 (1), p.317-327
• Main Authors: Matthews, Donald P, McCarthy, James R, Whitten, Jeffrey P, Kastner, Philip R, Barney, Charlotte L, Marshall, Franklin N, Ertel, Marcia A, Burkhard, Therese, Shea, Philip J, Kariya, Takashi
• Format: Article
• Language: English
• Subjects: 2',3'-Cyclic-Nucleotide Phosphodiesterases - antagonists & inhibitors; Amrinone - pharmacology; Animals; Blood Pressure - drug effects; Cardiotonic Agents; Chemical Phenomena; Chemistry; Dogs; Exact sciences and technology; Furans - chemical synthesis; Furans - pharmacology; Heart Rate - drug effects; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Imidazoles - chemical synthesis; Imidazoles - pharmacology; inotropism; Isoenzymes - antagonists & inhibitors; Milrinone; Molecular Structure; Myocardial Contraction - drug effects; Organic chemistry; Preparations and properties; Pyridones - pharmacology; Rats; Stimulation, Chemical; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - pharmacology; Thiophenes - chemical synthesis; Thiophenes - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00163a052

A series of substituted 2,2'-bi-1H-imidazoles and related analogues was synthesized and evaluated for inotropic activity. Structure-activity relationship studies based on a nonclassical bioisosteric approach indicated the necessity of a cyano group on one of the imidazole rings to obtain the desired pharmacological profile. 4(5)-Cyano-2,2'-bi-1H-imidazole (15a) was the most potent inotropic agent in the series. It produced a 25% increase in left ventricular dP/dt at 0.16 mg/kg iv (ED25% = 0.16 mg/kg) and increased left ventricular contractile force 60% at 1 mg/kg iv in anesthetized dogs. Compound 15a is a good inhibitor of type IV cyclic nucleotide phosphodiesterase isolated from dog heart having a potency similar to that of amrinone. Neither 5'-cyano-2,4'-bi-1H-imidazole (44) nor 4-cyano-2,4'-bi-1H-imidazole (48) demonstrated inotropic activity. In addition, the two possible 1,1'-dimethylcyano-2,2'-bi-1H-imidazoles (24 and 25) were inactive, indicating that an acidic NH as well as a cyano group are essential for inotropic activity.