Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors.

Abstract

The orally-active CYP17A1 inhibitor abiraterone acetate (AA) decreases adrenal and intratumoral androgen biosynthesis and is an effective agent for the treatment of prostate cancer. Abiraterone potently inhibits both reactions catalyzed by CYP17, the 17α-hydroxylase (hydroxylase) reaction as well as the 17,20-lyase (lyase) transformation. CYP17 hydroxylase inhibition prevents the synthesis of adrenal glucocorticoids and causes an accumulation of circulating mineralocorticoids. As a consequence of potent CYP17 hydroxylase inhibition (i.e., lack of lyase selectivity), AA must be co-administered with the cortisol replacement prednisone and patients may experience the effects of mineralocorticoid excess syndrome (MES). Herein, we describe rationally-designed, CYP17 lyase-selective inhibitors that could prove safer and more effective than abiraterone. Using proprietary methodology, the high-affinity pyridine or imidazole metal-binding group found in current clinical CYP17 inhibitors was replaced with novel, less avid, metal-binding groups in concert with potency-enhancing molecular scaffold modifications. This process produced a unique series of CYP17 lyase-selective inhibitors that included the oral agent 6 (VT-464), now in Phase 2 prostate cancer clinical trials. The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases.

• Authors: Stephen W Rafferty, Joel R Eisner, William R Moore, Robert J Schotzinger, William J Hoekstra
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 11 Pg. 2444-7 (Jun 01 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 24775307 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Triazoles
• Steroid 17-alpha-Hydroxylase

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Male
• Molecular Structure
• Prostatic Neoplasms (drug therapy, enzymology)
• Rats
• Steroid 17-alpha-Hydroxylase (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Triazoles (chemical synthesis, chemistry, pharmacology)