Wrigglesworth R, Walpole C S, Bevan S, Campbell E A, Dray A, Hughes G A, James I, Masdin K J, Winter J
Sandoz Institute for Medical Research, London, England.
J Med Chem. 1996 Dec 6;39(25):4942-51. doi: 10.1021/jm960512h.
Structural features of three regions of the capsaicin molecule necessary for agonist properties were delineated by a previously reported modular approach. These in vitro agonist effects were shown to correlate with analgesic potency in rodent models. Combination of optimal structural features from each of these regions of the capsaicin molecule have led to highly potent agonists (eg., 1b). Evaluation in vivo established that 1b had analgesic properties but poor oral activity, short duration of action, and excitatory side effects which precluded further development of this compound. Preliminary metabolism studies had shown that the phenol moiety of 1b was rapidly glucuronidated in vivo, providing a possible explanation for the poor pharmacokinetic profile. Subsequent specific modification of the phenol group led to compounds 2a-j, which retained in vitro potency. The in vivo profiles of two representatives of this series, 2a,h, were much improved over the "parent" phenol series, and they are candidates for development as analgesic agents.
通过先前报道的模块化方法描绘了辣椒素分子三个区域中激动剂特性所必需的结构特征。这些体外激动剂效应显示与啮齿动物模型中的镇痛效力相关。辣椒素分子这些区域中每个区域的最佳结构特征相结合产生了高效激动剂（例如1b）。体内评估表明1b具有镇痛特性，但口服活性差、作用持续时间短且有兴奋副作用，这排除了该化合物的进一步开发。初步代谢研究表明1b的酚部分在体内迅速葡糖醛酸化，这为不良药代动力学特征提供了一种可能的解释。随后对酚基团进行的特定修饰产生了化合物2a - j，它们保留了体外效力。该系列的两个代表物2a、h的体内特征比“母体”酚系列有了很大改善，它们是作为镇痛药开发的候选物。
