Identification of potent, soluble, and orally active TRPV1 antagonists

Paul Ratcliffe; John Maclean; Lynn Abernethy; Tom Clarkson; Maureen Dempster; Anna-Marie Easson; Darren Edwards; Katy Everett; Helen Feilden; Peter Littlewood; Duncan McArthur; Deborah McGregor; Hazel McLuskey; Olaf Nimz; Lesley-Anne Nisbet; Ronnie Palin; Heather Tracey; Glenn Walker

doi:10.1016/j.bmcl.2011.01.112

Identification of potent, soluble, and orally active TRPV1 antagonists

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2559-63. doi: 10.1016/j.bmcl.2011.01.112. Epub 2011 Jan 31.

Authors

Paul Ratcliffe¹, John Maclean, Lynn Abernethy, Tom Clarkson, Maureen Dempster, Anna-Marie Easson, Darren Edwards, Katy Everett, Helen Feilden, Peter Littlewood, Duncan McArthur, Deborah McGregor, Hazel McLuskey, Olaf Nimz, Lesley-Anne Nisbet, Ronnie Palin, Heather Tracey, Glenn Walker

Affiliation

¹ Department of Chemistry, MSD, Newhouse, Lanarkshire ML1 5SH, UK. Paul.Ratcliffe@grunenthal.com

PMID: 21435873
DOI: 10.1016/j.bmcl.2011.01.112

Abstract

Optimization of a water soluble, moderately potent lead series of isoxazole-3-carboxamides was conducted, affording a compound with the requisite balance of potency, solubility and physicochemical properties for in vivo use. Compound 8e was demonstrated to be efficacious in a rat model of inflammatory pain, following oral administration.

MeSH terms

Administration, Oral
Amides / chemical synthesis
Amides / chemistry
Amides / therapeutic use
Animals
Disease Models, Animal
Humans
Isoxazoles / chemical synthesis
Isoxazoles / chemistry*
Isoxazoles / therapeutic use
Pain / drug therapy
Rats
TRPV Cation Channels / antagonists & inhibitors*
TRPV Cation Channels / metabolism

Substances

Amides
Isoxazoles
TRPV Cation Channels
TRPV1 protein, human