Imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyrazines: the role of nitrogen position in inotropic activity.
Congestive heart failure is a major medical problem for which existing medicaments have provided limited benefit. Recent new experimental drugs, including imidazo[4,5-b]- and imidazo[4,5-c]pyridines, have both inotropic and vasodilatory properties. Subtle changes in nitrogen position of these compounds have been shown to dramatically affect potency. We have synthesized a series of imidazo[4,5-b]- and -[4,5-c]pyridine analogues having an imidazo nitrogen relocated at the bridgehead position. The superior inotropic activity of the [4,5-c]pyridines as compared to [4,5-b]pyridines is reaffirmed by the activity of our analogues. The biological equivalence of imidazo[4,5-b]pyridines with imidazo[1,2-a]pyrimidines and imidazo[4,5-c]pyridines with imidazo[1,2-a]pyrazines is demonstrated. Further, 2-[2-methoxy-4-(methylsulfenyl)phenyl]imidazo[1,2-a]pyrazine and 2-[2-methoxy-4-(methylsulfonyl)phenyl]-imidazo[1,2-a]pyrazine are potent inotropic agents both in vitro and in vivo.
Spitzer
W A
WA
Eli Lilly and Company, Indianapolis, Indiana 46285.
Victor
F
F
Pollock
G D
GD
Hayes
J S
JS
D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis*; D002415:Cats; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D011719:Pyrazines; D011743:Pyrimidines