Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17alpha-hydroxylase/17,20-lyase (P450(17alpha)).
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.
Patel
Chirag H
CH
Department of Pharmacy, School of Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey, KT1 2EE, UK.
Dhanani
Sachin
S
Owen
Caroline P
CP
Ahmed
Sabbir
S
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011374:Progesterone / Q000096:biosynthesis / Q000737:chemistry
D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D011374:Progesterone; C029899:imidazole; D003577:Cytochrome P-450 Enzyme System