Wright S W, Harris R R, Collins R J, Corbett R L, Green A M, Wadman E A, Batt D G
Inflammatory Diseases Research, Du Pont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0353.
J Med Chem. 1992 Aug 21;35(17):3148-55. doi: 10.1021/jm00095a009.
The synthesis, biological evaluation, and structure-activity relationships of a series of 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols are described. These compounds show potent dose-dependent topical antiinflammatory activity in murine models of skin inflammation. This effect is likely due to inhibition of cytochrome P450 and consequent reduction in levels of 12R-HETE in the skin. These compounds were examined for their ability to inhibit the oxidative metabolism of arachidonic acid; they specifically inhibit the formation of prostacyclins in mouse macrophages. To study the effects of structure on the in vivo activity, three general features of the molecules were varied: the position of attachment of the pyridine nucleus (A), the second aromatic residue (B), and the nitrogen base on the ethanol chain (C). 1-[4-(4-Pyridyl)phenyl]-1-(4-fluorophenyl)-2- imidazolylethanol (2a, DuP 983) shows a very attractive profile of antiinflammatory activity and has been selected for clinical evaluation as a topical antiinflammatory agent.
本文描述了一系列1-(吡啶基苯基)-1-苯基-2-咪唑基乙醇的合成、生物学评价及构效关系。这些化合物在小鼠皮肤炎症模型中表现出强效的剂量依赖性局部抗炎活性。这种作用可能是由于抑制了细胞色素P450，从而降低了皮肤中12R-HETE的水平。研究了这些化合物抑制花生四烯酸氧化代谢的能力；它们能特异性抑制小鼠巨噬细胞中前列环素的形成。为了研究结构对体内活性的影响，对分子的三个一般特征进行了改变：吡啶核的连接位置（A）、第二个芳香残基（B）以及乙醇链上的氮碱基（C）。1-[4-(4-吡啶基)苯基]-1-(4-氟苯基)-2-咪唑基乙醇（2a，DuP 983）显示出非常有吸引力的抗炎活性谱，已被选为局部抗炎剂进行临床评价。
