Synthesis and evaluation of 17-aliphatic heterocycle-substituted steroidal inhibitors of 17alpha-hydroxylase/C17-20-lyase (P450 17).

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Hartmann RW, Hector M, Wachall BG, Palusczak A, Palzer M, Huch V, Veith M

Synthesis and evaluation of 17-aliphatic heterocycle-substituted steroidal inhibitors of 17alpha-hydroxylase/C17-20-lyase (P450 17).

J Med Chem. 2000 Nov 16;43(23):4437-45.

PubMed ID

11087568 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Dazoxiben	Thromboxane-A synthase	IC 50 (nM)	1100	N/A	N/A	Details