Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability

The V1a receptor has emerged as an attractive target for a range of indications including Raynaud’s disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective...

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Published in:Bioorganic & medicinal chemistry letters 2011-10, Vol.21 (19), p.5684-5687
Main Authors: Johnson, Patrick S., Ryckmans, Thomas, Bryans, Justin, Beal, Dave M., Dack, Kevin N., Feeder, Neil, Harrison, Anthony, Lewis, Mark, Mason, Helen J., Mills, James, Newman, Julie, Pasquinet, Christelle, Rawson, Dave J., Roberts, Lee R., Russell, Rachel, Spark, Deborah, Stobie, Alan, Underwood, Toby J., Ward, Robin, Wheeler, Simon
Format: Article
Language:English
Subjects:
antagonists
Antidiuretic Hormone Receptor Antagonists
Benzodiazepines - chemical synthesis
Benzodiazepines - chemistry
Benzodiazepines - metabolism
Benzodiazepines - pharmacology
Biological and medical sciences
Cardiovascular system
Cytochrome P-450 Enzyme System - metabolism
Drug Design
Drug Discovery
Drug Stability
Dysmenorrhea - drug therapy
Female
Genital system. Reproduction
Hormone Antagonists - chemical synthesis
Hormone Antagonists - chemistry
Hormone Antagonists - metabolism
Hormone Antagonists - pharmacology
Humans
Lead optimisation
LiPE
Medical sciences
metabolism
Microsomes - physiology
Miscellaneous
Molecular Structure
Number of rotatable bonds
Pharmacology. Drug treatments
receptors
Triazoles
Triazoles - chemical synthesis
Triazoles - chemistry
Triazoles - metabolism
Triazoles - pharmacology
V1a antagonists
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Summary:The V1a receptor has emerged as an attractive target for a range of indications including Raynaud’s disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.08.038