title: Synthesis and cardiotonic activity of novel biimidazoles.
abstract: 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.
authors: Merrell Dow Research Institute, Cincinnati, Ohio 45215.
authors: D P
authors: DP
authors: Matthews
authors: J R
authors: JR
authors: McCarthy
authors: J P
authors: JP
authors: Whitten
authors: P R
authors: PR
authors: Kastner
authors: C L
authors: CL
authors: Barney
authors: F N
authors: FN
authors: Marshall
authors: M A
authors: MA
authors: Ertel
authors: T
authors: T
authors: Burkhard
authors: P J
authors: PJ
authors: Shea
authors: T
authors: T
authors: Kariya
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors; D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D020105:Milrinone; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology; D051381:Rats; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D005663:Furans; D007093:Imidazoles; D007527:Isoenzymes; D011728:Pyridones; D013844:Thiazoles; D013876:Thiophenes; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D020105:Milrinone; D000676:Amrinone