Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17α-hydroxylase/17,20-lyase (P45017α)

We report the preliminary results of the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of phenyl alkyl imidazole-based compounds as inhibitors of the two components of 17 alpha-hydroxylase/17,20-lyase (P450(17 alpha)), that is, 17 alpha-hydroxylase (17 alpha-OHase) and 17,20-lyase (lyase). The results show that N-3-(4-bromophenyl) propyl imidazole (12) (IC50 = 2.95 mu M against 17 alpha-OHase and IC50 = 0.33 mu M against lyase) is the most potent compound within the current study, in comparison to ketoconazole (KTZ) (IC50 = 3.76 mu M against 17 alpha-OHase and IC50 = 1.66 mu M against lyase). Modelling of these compounds suggests that the length of the alkyl chain enhances the interaction between the inhibitor and the area of the active site corresponding to the C(3) area of the steroid backbone, thereby increasing potency. (c) 2006 Elsevier Ltd. All rights reserved.