Substituted pyrazoles as novel sEH antagonist: Investigation of key binding interactions within the catalytic domain

A novel series of pyrazole sEH inhibitors is reported. Lead optimization efforts to replace the aniline core are also described. In particular, 2-pyridine, 3-pyridine and pyridazine analogs are potent sEH inhibitors with favorable CYP3A4 inhibitory and microsomal stability profiles.

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (22), p.6379-6383
Main Authors: Lo, Ho Yin, Man, Chuk C., Fleck, Roman W., Farrow, Neil A., Ingraham, Richard H., Kukulka, Alison, Proudfoot, John R., Betageri, Raj, Kirrane, Tom, Patel, Usha, Sharma, Rajiv, Hoermann, Mary Ann, Kabcenell, Alisa, Lombaert, Stéphane De
Format: Article
Language:English
Subjects:
Aniline
Anti-hypertension
Antihypertensive agents
Biological and medical sciences
Caco-2 Cells
Cardiovascular system
Catalytic Domain
Crystallography, X-Ray
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors
EETs
Enzyme Inhibitors - pharmacology
Epoxide Hydrolases - antagonists & inhibitors
Humans
Medical sciences
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Models, Molecular
Pharmacology. Drug treatments
Pyrazoles
Pyrazoles - pharmacology
sEH
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Description
Summary:A novel series of pyrazole sEH inhibitors is reported. Lead optimization efforts to replace the aniline core are also described. In particular, 2-pyridine, 3-pyridine and pyridazine analogs are potent sEH inhibitors with favorable CYP3A4 inhibitory and microsomal stability profiles.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.09.095