CYP17 Inhibitors. Annulations of Additional Rings in Methylene Imidazole Substituted Biphenyls: Synthesis, Biological Evaluation and Molecular Modelling

Twenty-one novel compounds originating from two classes of annulated biphenyls were synthesized as mimetics of the steroidal A- and C-rings and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of the hepatic CYP enzyme 3A4. Potent CYP17 inhibitors were found for each class, compound 9 (17 and 71% at 0.2 and 2 mu M, respectively) and 21 (591 nM). Compound 21 showed only weak inhibition of CYP3A4 (32 and 64% at 2 and 10 AM, respectively). Both compounds, however, exhibited moderate to Strong inhibition of the glucocorticoid-forming enzyme CYP11B1. The most interesting compounds were docked into our protein model. They bound into one of the modes which we have previously published. New interaction regions were identified.