Rw. Hartmann et al., Synthesis and evaluation of 17-aliphatic heterocycle-substituted steroidalinhibitors of 17 alpha-hydroxylase/C17-20-lyase (P450 17), J MED CHEM, 43(23), 2000, pp. 4437-4445
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, oxir
ane, thiirane, diaziridine, diazirine, azetidine) were introduced into the
17 beta -position of anstrost-5-en-3 beta -ol. After identifying that aziri
dine is the most suitable functional group to coordinate with the heme iron
, modifications of the steroidal skeleton were performed for further optimi
zation. 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 muM, K-i = 3 nM; IC50 hum
an: 0.54 muM, K-i = 8 nM), 5 (IC50 rat: 0.43 muM, K-i = 7 nM; IC50 human: 0
.29 muM, K-i = 4 nM), and 8 (21R:21S = 1:1; IC50 rat: 0.53 muM, K-i = 9 nM;
IC50 human: 0.40 muM, K-i = 6 nM) which were more potent than the referenc
e ketoconazole (IC50 rat: 67 muM; IC50 human: 0.74 muM), The inhibitory pot
ency 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, P4
50 sec, P450 TxA(2), and 5 alpha -reductase. Tested for in vivo activity, 3
and 8 (0.019 mmol/kg) decreased the plasma testosterone concentration in r
ats by 81% and 84% after 2 h.