Huang F C, Galemmo R A, Johnson W H, Poli G B, Morrissette M M, Mencel J J, Warus J D, Campbell H F, Nuss G W, Carnathan G W
Rorer Central Research, Horsham, Pennsylvania 19044.
J Med Chem. 1990 Apr;33(4):1194-200. doi: 10.1021/jm00166a017.
This series of reports describe the development of orally active, highly potent, specific antagonists of the peptidoleukotrienes containing a (2-quinolinylmethoxy)phenyl moiety. The compounds reported in this paper contain an additional phenyl ring, which has significantly improved the receptor affinity. The effect of changes in the linkage between the two phenyl rings as well as the orientation of the acidic functional group on biological activity are discussed. Many of these compounds have high affinity to the sulfidopeptide leukotriene D4 receptors with Ki values ranging between 2 and 20 nM and are orally active. Compound 27 [RG 12525, 5-[[2-[[4-(2-quinolinylmethoxy)phenoxy]- methyl]phenyl]methyl]-1H-tetrazole] represents the best combination of in vitro and in vivo biological activity in this series and has been selected for further evaluation in clinical studies of asthma.
本系列报告描述了含(2 - 喹啉基甲氧基)苯基部分的肽白三烯口服活性、高效、特异性拮抗剂的研发情况。本文报道的化合物含有一个额外的苯环，这显著提高了受体亲和力。讨论了两个苯环之间连接方式的改变以及酸性官能团的取向对生物活性的影响。这些化合物中的许多对硫肽白三烯D4受体具有高亲和力，Ki值在2至20 nM之间，且具有口服活性。化合物27 [RG 12525，5 - [[2 - [[4 - (2 - 喹啉基甲氧基)苯氧基]甲基]苯基]甲基]-1H - 四氮唑]代表了该系列中体外和体内生物活性的最佳组合，并已被选用于哮喘临床研究的进一步评估。
