Inhibitors of Steroidal Cytochrome P450 Enzymes as Targets for Drug Development
Eckhard Baston and Frederic R. Leroux
Affiliation: Laboratoire de Stereochimie (UMR CNRS 7509), Universite Louis Pasteur (ECPM), 25 rue Becquerel, F–67087 Strasbourg, France.
Cytochrome P450s are enzymes which catalyze a large number of biological reactions, for example hydroxylation, N-, O-, S- dealkylation, epoxidation or desamination. Their substrates include fatty acids, steroids or prostaglandins. In addition, a high number of various xenobiotics are metabolized by these enzymes. The enzyme 17α-hydroxylase-C17,20-lyase (P45017, CYP 17, androgen synthase), a cytochrome P450 monooxygenase, is the key enzyme for androgen biosynthesis. It catalyzes the last step of the androgen biosynthesis in the testes and adrenal glands and produces androstenedione and dehydroepiandrosterone from progesterone and pregnenolone. The microsomal enzyme aromatase (CYP19) transforms these androgens to estrone and estradiol. Estrogens stimulate tumor growth in hormone dependent breast cancer. In addition, about 80 percent of prostate cancers are androgen dependent. Selective inhibitors of these enzymes are thus important alternatives to treatment options like antiandrogens or antiestrogens. The present article deals with recent patents (focus on publications from 2000 - 2006) concerning P450 inhibitor design where steroidal substrates are involved. In this context a special focus is provided for CYP17 and CYP19. Mechanisms of action will also be discussed. Inhibitors of CYP11B2 (aldosterone synthase) will also be dealt with.
Keywords: Estrogen, androgen, 17α-hydroxylase-C17, 20-lyase, CYP 17, CYP 19, CYP11B2, steroidal inhibitors, nonsteroidal inhibitors, aromatase
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