Spitzer W A, Victor F, Pollock G D, Hayes J S
Eli Lilly and Company, Indianapolis, Indiana 46285.
J Med Chem. 1988 Aug;31(8):1590-5. doi: 10.1021/jm00403a018.
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.
充血性心力衰竭是一个重大的医学问题，现有药物对此提供的益处有限。最近的新型实验药物，包括咪唑并[4,5 - b] - 和咪唑并[4,5 - c]吡啶，具有正性肌力和血管舒张特性。已表明这些化合物氮位置的细微变化会显著影响效力。我们合成了一系列咪唑并[4,5 - b] - 和 - [4,5 - c]吡啶类似物，其中咪唑氮重新定位在桥头位置。我们类似物的活性再次证实了[4,5 - c]吡啶相对于[4,5 - b]吡啶具有更优越的正性肌力活性。证明了咪唑并[4,5 - b]吡啶与咪唑并[1,2 - a]嘧啶以及咪唑并[4,5 - c]吡啶与咪唑并[1,2 - a]吡嗪的生物学等效性。此外，2 - [2 - 甲氧基 - 4 - （甲基亚磺酰基）苯基]咪唑并[1,2 - a]吡嗪和2 - [2 - 甲氧基 - 4 - （甲基磺酰基）苯基]咪唑并[1,2 - a]吡嗪在体外和体内都是有效的正性肌力药物。
