Enantioselectivity of Some 1-[(Benzofuran-2-yl) phenylmethyl] imidazoles as Aromatase (P450_AROM) Inhibitors

Abstract

The enantioselectivity ratio ((+)-:(-)-forms) of three substituted 1-[(benzofuran-2-yI) phenylmethyl] imidazoles as inhibitors of aromatase (P450_AROM) was 2.16, 12.3 and 1.0 for the 4-methyl-, 4-fluoro- and 4-chloro-substituted compounds, respectively. The (±)-compounds were all >1000 times more potent than (±)-aminoglutethimide (IC₅₀ = 12 × 10³ nM). High potency (5.3–65.0 nM) for all the enantiomers studied is unusual since activity usually resides in one form for chiral inhibitors of P450_AROM- The 4-methyl derivative was fitted into the model [Furet, P., Batzl, C., Bhatnager, A.S., Francotte, E., Rihs, G. and Lang, M. (1993) J. Med. Chem. 36, pp. 1393–1400] for binding of S-(-)-fadrazole to the active site and the (R)- and (S)- forms both gave a good fitting pattern with (S)-(-)-fadrazole so accounting for their close activity. Docking of both forms into the active site model for P450_AROM [Laughton, C.A., Zvelebil, M.J.J.M. and Neidel, S. (1993) J. Steroid Biochem. Mol. Biol. 44, pp. 399–407], using the orientation of (S)-(±)-fadrazole, gave similar strong binding along the position of the C and D rings of the steroid substrate and in the hydrophobic cavity below the A/B rings. The site was probed for group size accommodation using the less potent 4-phenyl analogue (IC₅₀(±) = 242nM): the (S)-form showed restricted access to the region under the A ring due to the extended bulk of the biphenyl group.

Key Words:

• Aromatase
• P450_AROM
• Inhibition
• Enantioselectivity
• Docking
• Modelling