Synthesis, biochemical evaluation of a range of potent 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17α-hydroxylase/17,20-Lyase (P45017α)

We report the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of azole-based compounds as inhibitors of the two components of the cytochrome P-450 enzyme 17 alpha-hydroxylase/17,20-lyase (P450(17 alpha)), i.e. 17 alpha-hydroxylase (17 alpha-OHase) and 17,20-lyase (lyase). The results suggest that the compounds synthesised are potent inhibitors, with 7-phenyl heptyl imidazole (11) (IC50 = 320 nM against 17 alpha-OHase and IC50 = 100 nM against lyase); 1-[7-(4-fluorophenyl)heptyl] imidazole (14) (IC50 = 170 nM against 17 alpha-OHase and IC50 = 57 nM against lyase); 1-[5-(4-bromophenyl) pentyl] imidazole (19) (IC50 = 500 nM against 17 alpha-OHase and IC50 = 58 nM against lyase) being the most potent inhibitors within the current study, in comparison to ketoconazole (KTZ) K-50 = 3.76 mu M against 17 alpha-OHase and IC50 = 1.66 mu M against lyase). Furthermore, consideration of the inhibitory activity against the two components shows that all of the compounds tested are less potent owards the 17 alpha-OHase in comparison to the lyase component, a desirable property in the development of novel inhibitors of P450(17 alpha). From the modelling of these compounds onto the novel substrate heme complex (SHC) for the overall enzyme complex, the length of the compound, along with its ability to undergo interaction with the active site corresponding to the C(3) area of the steroidal backbone, are suggested to play a key role in determining the overall inhibitory activity. (c) 2008 Elsevier Ltd. All rights reserved.