Synthesis and biological evaluation of imidazole based compounds as cytochrome P-450 inhibitors.
Several phenyl ethyl and phenyl propyl imidazole based compounds have been synthesised and their biological activity evaluated against human placental Aromatase (AR), rat testicular 17 alpha-hydroxylase/ 17,20-lyase (P450(17) alpha) and bovine cholesterol side chain cleavage (CSCC). The compounds showed good selectivity towards AR with N-[2-(4'-Nitrophenyl) ethyl] imidazole (2) (IC50 = 0.16 +/- 0.01 microM, Ki = 0.09 +/- 0.01 microM), the most potent AR inhibitor, showing some 130 times greater potency over Aminoglutethimide (AG) (IC50 = 20.0 +/- 2.6 microM, Ki = 11.0 +/- 2.0 microM). N-[3-(4'-Fluorophenyl) propyl] imidazole (10) (IC50 = 0.31 +/- 0.01 microM, Ki = 0.34 +/- 0.05 microM), N-(2-(4'-Fluorophenyl ethyl) imidazole (5) (IC50 = 0.74 +/- 0.01 microM, Ki = 0.40 +/- 0.02 microM), N-(3-(4'-Chlorophenyl propyl) imidazole (9) (IC50 = 0.82 +/- 0.02 microM) and N-[3-(4'-Nitrophenyl) propyl] imidazole (7) (IC50 = 0.84 +/- 0.02 microM, Ki = 0.10 microM) were also more potent than AG. Of the compounds tested for P450(17) alpha activity, 7 (IC50 = 25.0 +/- 2.0 microM), N-[2-(4'-Aminophenyl) ethyl] imidazole (3) (IC50 = 27.6 +/- 0.10 microM), 9 (IC50 = 29.0 +/- 4.0 microM) and 2 (IC50 = 30.2 +/- 2.0 microM) showed the highest activity, possessing approximately half the activity of Ketoconazole (IC50 = 12.1 +/- 2.9 microM). Compounds 1, 2, 3, and 7 showed 0% inhibitory activity towards CSCC at 200 microM whilst AG showed 83% inhibition under the same conditions. The compounds proved themselves to be excellent lead compounds and supported the novel models developed by Ahmed for AR and P450(17) alpha.
Ahmed
S
S
Department of Pharmacy, Brighton University, UK.
Smith
J H
JH
Nicholls
P J
PJ
Whomsley
R
R
Cariuk
P
P
D000818:Animals; D047072:Aromatase Inhibitors; D002417:Cattle; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D010920:Placenta / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D047072:Aromatase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles