Synthesis, Biological Evaluation, and Molecular Modeling of Abiraterone Analogues: Novel CYP17 Inhibitors for the Treatment of Prostate Cancer
- 1 August 2008
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 51 (16), 5009-5018
- https://doi.org/10.1021/jm800355c
Abstract
Abiraterone, a steroidal cytochrome P450 17alpha-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 (IC50 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.Keywords
This publication has 41 references indexed in Scilit:
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- Advances in the Treatment of Prostate CancerAnnual Review of Medicine, 2007
- Phase II study of mitoxantrone and ketoconazole for hormone‐refractory prostate cancerCancer, 2006
- Antiandrogen Withdrawal Alone or in Combination With Ketoconazole in Androgen-Independent Prostate Cancer Patients: A Phase III Trial (CALGB 9583)Journal of Clinical Oncology, 2004
- Low Dose Ketoconazole With Replacement Doses of Hydrocortisone in Patients With Progressive Androgen Independent Prostate CancerJournal of Urology, 2002
- Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trialsThe Lancet, 2000
- Biochemistry and pharmacokinetics of potent non-steroidal cytochrome P45017α inhibitorsThe Journal of Steroid Biochemistry and Molecular Biology, 1997
- 3- and 4-Pyridylalkyl Adamantanecarboxylates: Inhibitors of Human Cytochrome P45017α (17α-Hydroxylase/C17,20-Lyase). Potential Nonsteroidal Agents for the Treatment of Prostatic CancerJournal of Medicinal Chemistry, 1996
- Esters of 3-Pyridylacetic Acid That Combine Potent Inhibition of 17.alpha.-Hydroxylase/C17,20-Lyase (Cytochrome P45017.alpha.) with Resistance to Esterase HydrolysisJournal of Medicinal Chemistry, 1995
- Three-Month Treatment With a Long-Acting Gonadotropin-Releasing Hormone Agonist of Patients With Benign Prostatic Hyperplasia: Effects on Tissue Androgen Concentration, 5α-Reductase Activity and Androgen Receptor Content*Journal of Clinical Endocrinology & Metabolism, 1989