Abstract
A novel naphthylmethylimidazole derivative 1 and its related compounds were identified as 17,20-lyase inhibitors. Based on the structure-activity relationship around the naphthalene scaffold and the results of a docking study of 1a in the homology model of 17,20-lyase, the 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivative (+)-3c was synthesized and identified as a potent and highly selective 17,20-lyase inhibitor. Biological evaluation of (+)-3c at a dose of 1mg/kg in a male monkey model revealed marked reductions in both serum testosterone and dehydroepiandrosterone concentrations. Therefore, (+)-3c (termed orteronel [TAK-700]) was selected as a candidate for clinical evaluation and is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Crystallography, X-Ray
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Dehydroepiandrosterone / blood
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Haplorhini
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Inhibitory Concentration 50
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Magnetic Resonance Spectroscopy
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Male
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Models, Molecular
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Molecular Dynamics Simulation
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Naphthalenes / chemical synthesis
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Naphthalenes / chemistry
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Naphthalenes / pharmacology*
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Prostatic Neoplasms / blood
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / enzymology
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Stereoisomerism
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Steroid 17-alpha-Hydroxylase / antagonists & inhibitors*
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Structure-Activity Relationship
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Testosterone / blood
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Imidazoles
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Naphthalenes
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Testosterone
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Dehydroepiandrosterone
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Steroid 17-alpha-Hydroxylase