Pinto - J Med Chem 2008 51 50095018 5009 Synthesis...

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Synthesis, Biological Evaluation, and Molecular Modeling of Abiraterone Analogues: Novel CYP17 Inhibitors for the Treatment of Prostate Cancer Mariano A. E. Pinto-Bazurco Mendieta, Matthias Negri, Carsten Jagusch, Ursula Mu ¨ller-Vieira, Thomas Lauterbach, § and Rolf W. Hartmann* ,† Pharmaceutical and Medicinal Chemistry, Saarland Uni V ersity, P.O. Box 151150, D-66041 Saarbru ¨cken, Germany, Pharmacelsus CRO, Science Park 2, D-66123 Saarbru ¨cken, Germany, and Schwarz Pharma, Alfred-Nobel-Strasse 10, D-40789 Monheim, Germany Recei V ed March 29, 2008 Abiraterone, a steroidal cytochrome P450 17 R -hydroxylase-17,20-lyase inhibitor (CYP17), is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen-dependent prostate cancer. Since steroidal compounds often show side effects attributable to their structure, we have tried to replace the sterane scaffold by nonsteroidal core structures. The design and synthesis of 20 new abiraterone mimetics are described. Their activities have been tested with recombinant human CYP17 expressed in E. coli . Promising compounds were further evaluated for selectivity against CYP11B1, CYP11B2, and the hepatic CYP3A4. Compounds 19 and 20 showed comparable activity to abiraterone (IC 50 values of 144 and 64 nM vs 72 nM) and similar or even better selectivity against the other CYP enzymes. Selected compounds were also docked into our homology model, and the same binding modes as for abiraterone were found. Introduction Prostate cancer (PC a ) is the most common tumor and age- related cause of death in elder men worldwide. 1 Because of the advanced age of the patients, less invasive approaches are needed. Accordingly, the treatment of choice is “watchful waiting”, 2 followed by radiation therapy only when it is necessary. Since PC is androgen dependent in over 80% of the cases, another current standard treatment is orchiectomy, the surgical removal of the testes, usually applied to patients under 70 years old. The reduction of testicular androgen production by gonadotropin-releasing hormone (GnRH) analogues, 3 a “medical castration”, is often preferred over the surgical one and can also be used for treating older patients. Nevertheless, castration whether surgical or medical reduces maximally 90 - 95% of the daily testosterone production, which is often not enough to stop the tumor from growing, since prostate levels of testosterone and dihydrotestosterone are still about 25% and 10%, respectively, even after three months of treatment with a GnRH agonist. 4 The remaining 5 - 10% of the androgens are produced in the adrenals. In the 1980s, Labrie 5 hypothesized that additionally counteracting adrenal androgens by application of antiandrogens would further inhibit tumor growth. This approach, known as “combined androgen blockade” (CAB), has been widely used in the past. The results have been partially positive, especially in patients with minimal disease and good performance status.
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Pinto - J Med Chem 2008 51 50095018 5009 Synthesis...

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