Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])

Patel, Chirag H., Dhanani, Sachin, Owen, Caroline P. and Ahmed, Sabbir (2006) Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha]). Bioorganic & Medicinal Chemistry Letters, 16(18), pp. 4752-4756. ISSN (print) 0960-894X

Official URL: http://dx.doi.org/10.1016/j.bmcl.2006.06.092

Abstract

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 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results show that N-3-(4-bromophenyl) propyl imidazole (12) (IC50 = 2.95 microM against 17alpha-OHase and IC50 = 0.33 microM against lyase) is the most potent compound within the current study, in comparison to ketoconazole (KTZ) (IC50 = 3.76 microM against 17alpha-OHase and IC50 = 1.66 microM 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 C3 area of the steroid backbone, thereby increasing potency.

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