新型5α-还原酶抑制剂：苯氧基苯甲酰基苯基乙酸的合成、构效关系研究及药代动力学特征

Novel 5alpha-reductase inhibitors: synthesis, structure-activity studies, and pharmacokinetic profile of phenoxybenzoylphenyl acetic acids.

作者信息

Salem Ola I A, Frotscher Martin, Scherer Christiane, Neugebauer Alexander, Biemel Klaus, Streiber Martina, Maas Ruth, Hartmann Rolf W

机构信息

Pharmaceutical and Medicinal Chemistry, Saarland University, D-66041 Saarbrücken, Germany.

出版信息

J Med Chem. 2006 Jan 26;49(2):748-59. doi: 10.1021/jm050728w.

DOI:10.1021/jm050728w

PMID:16420060

Abstract

Novel substituted benzoyl benzoic acids and phenylacetic acids 1-14 have been synthesized and evaluated for inhibition of rat and human steroid 5alpha-reductase isozymes 1 and 2. The compounds turned out to be potent and selective human type 2 enzyme inhibitors, exhibiting IC(50) values in the nanomolar range. The phenylacetic acid derivatives were more potent than the analogous benzoic acids. Bromination in the 4-position of the phenoxy moiety led to the strongest inhibitor in this class (12; IC(50) = 5 nM), which was equipotent to finasteride. Since oral absorption is essential for a potential drug, 12 was further examined. In the parallel artificial membrane permeation assay (PAMPA) it turned out to be a good permeator, whereas it was a medium permeator in Caco2 cells. After oral administration (40 mg/kg) to rats a high bioavailability and a biological half-life of 5.5 h were observed, making it a promising candidate for clinical evaluation.

摘要

新型取代苯甲酰基苯甲酸和苯乙酸1-14已被合成，并对其抑制大鼠和人甾体5α-还原酶同工酶1和2的活性进行了评估。结果表明，这些化合物是强效且选择性的人2型酶抑制剂，其IC(50)值在纳摩尔范围内。苯乙酸衍生物比类似的苯甲酸更有效。苯氧基部分4位的溴化导致该类中最强的抑制剂（12；IC(50)=5 nM），其效力与非那雄胺相当。由于口服吸收对于潜在药物至关重要，因此对12进行了进一步研究。在平行人工膜渗透试验（PAMPA）中，它被证明是一种良好的渗透剂，而在Caco2细胞中它是一种中等渗透剂。给大鼠口服给药（40 mg/kg）后，观察到其具有高生物利用度和5.5小时的生物半衰期，使其成为临床评估的有希望的候选药物。