Hartmann R W, Hector M, Wachall B G, Palusczak A, Palzer M, Huch V, Veith M
Pharmaceutical and Medicinal Chemistry and Inorganic Chemistry, University of the Saarland, P.O. Box 151150, D-66041 Saarbrücken, Germany.
J Med Chem. 2000 Nov 16;43(23):4437-45. doi: 10.1021/jm991070n.
In the search for potent inhibitors of P450 17, the key enzyme in androgen biosynthesis, a series of steroidal inhibitors were synthesized and tested toward rat and human P450 17. Small aliphatic heterocycles (aziridine, oxirane, thiirane, diaziridine, diazirine, azetidine) were introduced into the 17beta-position of anstrost-5-en-3beta-ol. After identifying that aziridine is the most suitable functional group to coordinate with the heme iron, modifications of the steroidal skeleton were performed for further optimization. A wide range of inhibitory potencies toward P450 17 were found for the 21 test compounds. The most potent inhibitors toward the human and rat enzyme were aziridine compounds 3 (IC(50) rat: 0.21 microM, K(i) = 3 nM; IC(50) human: 0.54 microM, K(i) = 8 nM), 5 (IC(50) rat: 0.43 microM, K(i) = 7 nM; IC(50) human: 0.29 microM, K(i) = 4 nM), and 8 (21R:21S = 1:1; IC(50) rat: 0.53 microM, K(i) = 9 nM; IC(50) human: 0.40 microM, K(i) = 6 nM) which were more potent than the reference ketoconazole (IC(50) rat: 67 microM; IC(50) human: 0.74 microM). The inhibitory potency depends markedly on the stereochemistry at C20 of the inhibitors. This effect is more pronounced for the rat enzyme. Tested for selectivity, the highly potent inhibitors show poor inhibitory activity toward P450 arom, P450 scc, P450 TxA(2), and 5alpha-reductase. Tested for in vivo activity, 3 and 8 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats by 81% and 84% after 2 h.
在寻找雄激素生物合成中的关键酶——细胞色素P450 17的强效抑制剂的过程中，合成了一系列甾体抑制剂，并对大鼠和人细胞色素P450 17进行了测试。将小脂肪族杂环（氮丙啶、环氧乙烷、硫杂环丙烷、二氮丙啶、二氮烯、氮杂环丁烷）引入雄甾-5-烯-3β-醇的17β位。在确定氮丙啶是与血红素铁配位的最合适官能团后，对甾体骨架进行修饰以进一步优化。21种测试化合物对细胞色素P450 17表现出广泛的抑制活性。对人和大鼠酶最具活性的抑制剂是氮丙啶化合物3（大鼠IC50：0.21μM，Ki = 3 nM；人IC50：0.54μM，Ki = 8 nM）、5（大鼠IC50：0.43μM，Ki = 7 nM；人IC50：0.29μM，Ki = 4 nM）和8（21R:21S = 1:1；大鼠IC50：0.53μM，Ki = 9 nM；人IC50：0.40μM，Ki = 6 nM），它们比参考药物酮康唑（大鼠IC50：67μM；人IC50：0.74μM）更具活性。抑制活性明显取决于抑制剂C20位的立体化学。这种效应在大鼠酶中更为明显。经选择性测试，这些高效抑制剂对细胞色素P450芳香酶、细胞色素P450侧链裂解酶、细胞色素P450血栓素A2合酶和5α-还原酶的抑制活性较差。经体内活性测试，3和8（0.019 mmol/kg）在2小时后使大鼠血浆睾酮浓度分别降低了81%和84%。
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