Boyle F T, Gilman D J, Gravestock M B, Wardleworth J M
ICI Pharmaceuticals Division, Macclesfield, Cheshire, England.
Ann N Y Acad Sci. 1988;544:86-100. doi: 10.1111/j.1749-6632.1988.tb40391.x.
Antifungal azole derivatives are known to have potential for inhibition of host P-450 systems, and, in the attempts to increase the antifungal specificity of the inhibitor by identification of extra receptor binding within the enzyme complex, initial synthesis was guided by the structural requirements of the natural lanosterol substrate. With the aid of computer graphics, the 3'-styryl functionality was identified as a key structural element. For metabolically stable systems, in vitro-in vivo correlations exist, but optimizing oral activity resulted in the production of compounds with unacceptably long elimination half-lives. A disconnection of this relationship was achieved in pairs of structural isosteres with metabolic nonequivalence (CN:CONH2/OCH3:OCF3) and led to the identification of ICI 195,739, a novel 3'-tetrafluoropropoxystyryl-substituted bistriazole tertiary alcohol, as the compound of choice.
已知抗真菌唑衍生物具有抑制宿主P-450系统的潜力，并且在试图通过鉴定酶复合物内的额外受体结合来提高抑制剂的抗真菌特异性时，最初的合成是由天然羊毛甾醇底物的结构要求指导的。借助计算机图形学，3'-苯乙烯基官能团被确定为关键结构元素。对于代谢稳定的系统，存在体外-体内相关性，但优化口服活性导致产生消除半衰期长得不可接受的化合物。在具有代谢不等效性的结构电子等排体对（CN:CONH2/OCH3:OCF3）中实现了这种关系的断开，从而鉴定出ICI 195,739，一种新型的3'-四氟丙氧基苯乙烯基取代的双三唑叔醇，作为首选化合物。
