Haidar Samer, Ehmer Peter B, Barassin Stephan, Batzl-Hartmann Christine, Hartmann Rolf W
Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbrücken, Germany.
J Steroid Biochem Mol Biol. 2003 Apr;84(5):555-62. doi: 10.1016/s0960-0760(03)00070-0.
Aiming at the development of new drugs for the treatment of prostate cancer, the effects of steroidal compounds and one non-steroidal substance on androgen biosynthesis were evaluated in vitro and in vivo. Sa 40 [17-(5-pyrimidyl)androsta-5,16-diene-3beta-ol], its 3-acetyl derivate Sa 41 and BW 19 [3,4-dihydro-2-(4-imidazolylmethyl)-6-methoxy-1-methyl-naphthalene] are compounds from our group, which have been developed as inhibitors of CYP 17 (17alpha-hydroxylase-C17, 20-lyase, the key enzyme in androgen biosynthesis). They have been compared with CB 7598 [abiraterone: 17-(3-pyridyl)androsta-5,16-diene-3beta-ol], its 3-acetyl compound CB 7630 and ketoconazole, compounds which already have been used clinically. The most potent compound toward human CYP 17 (testicular microsomes) was Sa 40 (IC(50) value of 24 nM), followed by Sa 41, CB 7598, BW 19, CB 7630 and ketoconazole. Sa 40 shows a type II difference spectrum and a non-competitive type of inhibition (K(i) value of 16 nM). No recovery of enzyme activity was observed after preincubation of CYP 17 with Sa 40 and subsequent charcoal treatment. In Escherichia coli cells coexpressing human CYP 17 and NADPH-P450 reductase, Sa 40 was more active than CB 7598 and BW 19, whereas the acetyl compounds were not active. The latter three compounds were equally active towards rat CYP 17. Male Sprague-Dawley (SD) rats were administered daily for 14 days BW 19 and the acetyl derivatives Sa 41 and CB 7630 as prodrugs (0.1 mmol/kg intraperitoneally). The test compounds strongly reduced plasma testosterone concentration, as well as prostate and seminal vesicles weights. They showed moderate inhibitory effects on the weights of levator ani, bulbocavernosus and testes, whereas they led to an increase in adrenal and pituitary weights. The only exception was BW 19 which did not change pituitary weights. Based on its superiority on the human enzyme, it was concluded that Sa 40 in its 3beta-acetate form (Sa 41) could be a promising candidate for clinical evaluation.
为开发治疗前列腺癌的新药，在体外和体内评估了甾体化合物和一种非甾体物质对雄激素生物合成的影响。Sa 40 [17-(5-嘧啶基)雄甾-5,16-二烯-3β-醇]、其3-乙酰衍生物Sa 41和BW 19 [3,4-二氢-2-(4-咪唑基甲基)-6-甲氧基-1-甲基萘]是我们团队研发的化合物，已被开发作为CYP 17（17α-羟化酶-C17,20-裂解酶，雄激素生物合成中的关键酶）的抑制剂。将它们与CB 7598 [阿比特龙：17-(3-吡啶基)雄甾-5,16-二烯-3β-醇]、其3-乙酰化合物CB 7630和酮康唑进行了比较，这些化合物已在临床上使用。对人CYP 17（睾丸微粒体）最有效的化合物是Sa 40（IC(50)值为24 nM），其次是Sa 41、CB 7598、BW 19、CB 7630和酮康唑。Sa 40显示出II型差异光谱和非竞争性抑制类型（K(i)值为16 nM）。用Sa 40预孵育CYP 17并随后进行活性炭处理后，未观察到酶活性的恢复。在共表达人CYP 17和NADPH-P450还原酶的大肠杆菌细胞中，Sa 40比CB 7598和BW 19更具活性，而乙酰化合物则无活性。后三种化合物对大鼠CYP 17的活性相同。雄性Sprague-Dawley（SD）大鼠连续14天每天腹腔注射BW 19以及作为前药的乙酰衍生物Sa 41和CB 7630（0.1 mmol/kg）。受试化合物强烈降低血浆睾酮浓度以及前列腺和精囊重量。它们对提肛肌、球海绵体肌和睾丸重量显示出中等抑制作用，而导致肾上腺和垂体重量增加。唯一的例外是BW 19，其未改变垂体重量。基于其在人酶方面的优势，得出结论：3β-乙酸酯形式的Sa 40（Sa 41）可能是临床评估的有前途的候选药物。
