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

Ho Yin Lo; Chuk C Man; Roman W Fleck; Neil A Farrow; Richard H Ingraham; Alison Kukulka; John R Proudfoot; Raj Betageri; Tom Kirrane; Usha Patel; Rajiv Sharma; Mary Ann Hoermann; Alisa Kabcenell; Stéphane De Lombaert

doi:10.1016/j.bmcl.2010.09.095

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

Bioorg Med Chem Lett. 2010 Nov 15;20(22):6379-83. doi: 10.1016/j.bmcl.2010.09.095. Epub 2010 Sep 19.

Authors

Ho Yin Lo¹, Chuk C Man, Roman W Fleck, Neil A Farrow, Richard H Ingraham, Alison Kukulka, John R Proudfoot, Raj Betageri, Tom Kirrane, Usha Patel, Rajiv Sharma, Mary Ann Hoermann, Alisa Kabcenell, Stéphane De Lombaert

Affiliation

¹ Boehringer Ingelheim Pharmaceuticals Inc., Biomolecular Screening, 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877, USA. ho-yin.lo@boehringer-ingelheim.com

PMID: 20934334
DOI: 10.1016/j.bmcl.2010.09.095

Abstract

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.

MeSH terms

Caco-2 Cells
Catalytic Domain
Crystallography, X-Ray
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors
Enzyme Inhibitors / pharmacology*
Epoxide Hydrolases / antagonists & inhibitors*
Humans
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Models, Molecular
Pyrazoles / pharmacology*

Substances

Cytochrome P-450 CYP3A Inhibitors
Enzyme Inhibitors
Pyrazoles
Cytochrome P-450 CYP3A
CYP3A4 protein, human
Epoxide Hydrolases