Four 1-[(benzofuran-2-yl)methyl]imidazoles (1-4) have been evaluated as in-vitro inhibitors of human testicular and bovine adrenal microsomal 17 alpha-hydroxylase: 17,20-lyase (P450 17) as potential anti-prostatic agents. Their specificity towards other steroidogenic and liver enzymes has been compared with that of ketoconazole. All four compounds were inhibitors of the testicular enzyme (2, IC50 (concentration resulting in 50% inhibition) 0.185 microM; 4, IC50 0.18 microM) but less potent than ketoconazole (IC50 0.03 microM). Towards bovine adrenal enzyme 2 and 4 were 35- and 31-fold more potent than ketoconazole (IC50 = 39.8 microM). Compound 2 is a useful lead compound but although less potent than ketoconazole towards P450SCC and P450 11 beta, but not P450C21, at the enhanced dose required for equivalent effects in-vivo on P450 17 it is likely that cortisol and aldosterone production will be affected to a greater extent than with ketoconazole.
Cytochrome P450-mediated 4-hydroxylation of retinoic acid is an important pathway in the termination of its biological action and the activity of certain P450 isozymes has been studied in non-induced male rat hepatic microsomes using isozyme-selective inhibitors. The importance of the activity of the isozyme to retinoic acid metabolism was, 2A6 (diethyl dithiocarbamate as selective inhibitor) > 1A1/1A2 (7,8-benzoflavone) >> 1A1 (ellipticine) > 3A4 (naringenin, ketoconazole) as shown by the respective apparent IC50 values of 0.12, 0.34, 2.7, 9.25 and 13.5 microM with 2C8-10, 2D6 and 2E1 having little effect on metabolism. It is concluded that although the P450 3A family normally constitutes half the total rat hepatic P450 activity, other hepatic isozymes (1A1, 1A2 and 2A6) are also involved in retinoic acid metabolism. This suggests that the horizons for the design of potential anticancer agents acting through inhibition of retinoic acid metabolism may be widened to include structures which do not resemble the established hetereocyclic base P450 3A4 inhibitors.
Significant differences between the metabolism of retinoic acid by different tissues might be an important determinant of the effectiveness of a systemically administered inhibitor at a particular tissue site. Here the metabolism of retinoic acid has been studied in microsomal fractions from different tissues (liver, kidney, intestinal mucosa, lung, skin, brain) of the male rat to determine their relative metabolic activity. Kinetic analysis revealed major differences between the activity of different tissue microsomes. This is shown by the Vmax values for the metabolism of retinoic acid-liver (102+/-39.0 pmol (mg protein)(-1) min(-1)) was 100 times more active than the lung (1+/-0.03 pmol (mg protein)(-1) min(-1)), which was the least active. The range of Km values for microsomes from the different tissues was narrow (0.48-1.40 microM). Taking into account the mass of the tissue, the gross activity ranking for metabolism of retinoic acid was liver >> skin = kidney > brain > intestinal mucosa >> lung. It is concluded that metabolism of administered retinoic acid occurs mainly in the liver but that cellular retinoic acid levels in some other tissues (skin, kidney, brain) could be reduced (metabolized) to such an extent that higher levels might be observed after the use of inhibitors of retinoic acid metabolism.
The low stereospecificity of the enantiomers of 1-[(benzofuran-2-yl)-4-chlorophenylmethyl]imidazole (6, R=H, R'=4'-Cl) and the corresponding 4-fluoro compound as inhibitors of aromatase (P450Arom) has been explored using 1-(5,7-dichlorobenzofuran-2-yl)-1-(1H-imidaz-1-yl)ethane (7, R1=R2=Cl, R=CH3), -propane (7, R1=R2=Cl, R=C2H5), and the corresponding 5,7-dibromo compounds resolved as their dibenzoyl-D (or -L) tartrates. Low enantioselectivity ratios of 4.8 (5,7-diCl) and 12.6 (5,7-diBr) were shown for the ethanes. The values for the corresponding propanes were 8.3 and 5.2, respectively, and for these compounds the stereoselectivity was reversed.
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