ABSTRACT In April 2011, abiraterone acetate (Zytiga; Centocor Ortho Biotech), in combination with prednisone, was approved by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel.
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ABSTRACT: Steroidal compounds having a 17-(3-pyridyl) substituent together with a 16,17-double bond have been synthesized, using a palladium-catalyzed cross-coupling reaction of a 17-enol triflate with diethyl(3-pyridyl)borane, which are potent inhibitors of human testicular 17 alpha-hydroxylase-C17,20-lyase. The requirement for these structural features is stringent: compounds having 2-pyridyl (9), 4-pyridyl (10), or 2-pyridylmethyl (11) substituents instead of the 3-pyridyl substituent were either poor inhibitors or noninhibitory. Reduction of the 16,17-double bond to give 17 beta-pyridyl derivatives diminished potency with 3-pyridyl substitution (3-->27; IC50 for lyase, 2.9-->23 nM) but increased it with a 4-pyridyl substituent present (10-->28; IC50 1 microM-->53 nM). In contrast, a variety of substitution patterns in rings A-C of the steroid skeleton afforded inhibitors having potencies similar to those most closely related structurally to the natural substrates pregnenolone and progesterone, respectively 17-(3-pyridyl)androsta-5,16-dien-3 beta-ol (3, Kiapp < 1 nM; IC50 for lyase, 2.9 nM) and 17-(3-pyridyl)androsta-4,16-dien-3-one (15; IC50 for lyase, 2.1 nM). Thus compounds having variously aromatic ring A (18), saturated rings A/B (21, 22), and oxygenated ring C (26) exhibited IC50 values for lyase (1.8-3.0 nM) falling within a 2-fold range. The most potent compounds are candidates for development as drugs for the treatment of hormone-dependent prostatic carcinoma.Journal of Medicinal Chemistry 06/1995; 38(13):2463-71. · 5.61 Impact Factor
- BJU International 01/2006; 96(9):1241-6. · 3.05 Impact Factor
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ABSTRACT: Efficacy equivalent to that reported in other common adult solid tumors considered to be chemotherapy-sensitive has been reported with Docetaxel in patients with castrate-resistant prostate cancer. However, in contrast to other cancers, the expected increase in efficacy with the use of chemotherapy in earlier disease states has not been reported to date in prostate cancer. On the basis of these observations, we speculated that the therapy development paradigm used successfully in other cancers may not apply to the majority of prostate cancers. Several lines of supporting clinical and experimental observations implicate the tumor microenvironment in prostate carcinogenesis and resistance to therapy. We conclude that a foundation to guide the development of therapy for prostate cancer is required. The therapy paradigm we propose accounts for the central role of the tumor microenvironment in bone and, if correct, will lead to microenvironment-targeted therapy.Clinical Cancer Research 02/2010; 16(4):1100-7. · 7.84 Impact Factor