Synthesis and cardiotonic activity of novel biimidazoles.
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.
Matthews
D P
DP
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
McCarthy
J R
JR
Whitten
J P
JP
Kastner
P R
PR
Barney
C L
CL
Marshall
F N
FN
Ertel
M A
MA
Burkhard
T
T
Shea
P J
PJ
Kariya
T
T
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
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