Replacement of imidazolyl by pyridyl in biphenylmethylenes results in selective CYP17 and dual CYP17/CYP11B1 inhibitors for the treatment of prostate cancer.

摘要: Androgens are well-known to stimulate prostate cancer (PC) growth. Thus, blockade of androgen production in testes and adrenals by CYP17 inhibition is a promising strategy for the treatment PC. Moreover, many PC patients suffer from glucocorticoid overproduction, importantly mutated receptors can be stimulated glucocorticoids. In this study, first dual inhibitor CYP11B1 (the enzyme responsible last step biosynthesis) described. A series biphenylmethylene pyridines has been designed, synthesized, tested as inhibitors. The most active compounds were also selectivity against CYP11B2 (aldosterone synthase), CYP19 (aromatase), hepatic CYP3A4. detail, compound 6 was identified CYP17/CYP11B1 (IC50 values 226 287 nM) showing little other enzymes well 9 selective, highly potent = 52 exceeding abiraterone terms of...