Synthesis and Evaluation of 17-Aliphatic Heterocycle-Substituted Steroidal Inhibitors of 17α-Hydroxylase/C17−20-Lyase (P450 17)

• Published in: Journal of medicinal chemistry Vol. 43; no. 23; pp. 4437 - 4445
• Main Authors: Hartmann, Rolf W, Hector, Markus, Wachall, Bertil G, Palusczak, Anja, Palzer, Martina, Huch, Volker, Veith, Michael
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.11.2000; Amer Chemical Soc
• Subjects: Biological and medical sciences; Chemistry, Medicinal; Hormones. Endocrine system; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; IN-VITRO; POTENTIAL AGENTS; BIOSYNTHESIS; ENZYMES; P450 17; 17-ALPHA-HYDROXYLASE-C-17,C-20-LYASE; CYTOCHROME B; AROMATASE; DERIVATIVES; CANCER; Human; Steroid; Rat; Enzyme; Nitrogen heterocycle; Cytochrome P450; Rodentia; Three membered ring; Enzyme inhibitor; Steroid 17α-monooxygenase; Aziridine derivatives; In vitro; In vivo; Vertebrata; Mammalia; Structure activity relation; Animal; Pregnene derivatives; Oxidoreductases; Androstene derivatives; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• 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 17β-position of anstrost-5-en-3β-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 (IC50 rat:  0.21 μM, K i = 3 nM; IC50 human:  0.54 μM, K i = 8 nM), 5 (IC50 rat:  0.43 μM, K i = 7 nM; IC50 human:  0.29 μM, K i = 4 nM), and 8 (21R:21S = 1:1; IC50 rat:  0.53 μM, K i = 9 nM; IC50 human:  0.40 μM, K i = 6 nM) which were more potent than the reference ketoconazole (IC50 rat:  67 μM; IC50 human: 0.74 μM). 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 TxA2, and 5α-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.