title: Structure-activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists.
abstract: Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
authors.affiliation: Department of Chemistry, MSD, Newhouse, Lanarkshire, UK. ronnie.palin@gmail.com
authors.forename: Ronald
authors.initials: R
authors.lastname: Palin
authors.forename: Lynn
authors.initials: L
authors.lastname: Abernethy
authors.forename: Nasrin
authors.initials: N
authors.lastname: Ansari
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cameron
authors.forename: Tom
authors.initials: T
authors.lastname: Clarkson
authors.forename: Maureen
authors.initials: M
authors.lastname: Dempster
authors.forename: David
authors.initials: D
authors.lastname: Dunn
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Easson
authors.forename: Darren
authors.initials: D
authors.lastname: Edwards
authors.forename: John
authors.initials: J
authors.lastname: Maclean
authors.forename: Katy
authors.initials: K
authors.lastname: Everett
authors.forename: Helen
authors.initials: H
authors.lastname: Feilden
authors.forename: Koc-Kan
authors.initials: KK
authors.lastname: Ho
authors.forename: Steve
authors.initials: S
authors.lastname: Kultgen
authors.forename: Peter
authors.initials: P
authors.lastname: Littlewood
authors.forename: Duncan
authors.initials: D
authors.lastname: McArthur
authors.forename: Deborah
authors.initials: D
authors.lastname: McGregor
authors.forename: Hazel
authors.initials: H
authors.lastname: McLuskey
authors.forename: Irina
authors.initials: I
authors.lastname: Neagu
authors.forename: Stuart
authors.initials: S
authors.lastname: Neale
authors.forename: Lesley-Anne
authors.initials: LA
authors.lastname: Nisbet
authors.forename: Michael
authors.initials: M
authors.lastname: Ohlmeyer
authors.forename: Quynhchi
authors.initials: Q
authors.lastname: Pham
authors.forename: Paul
authors.initials: P
authors.lastname: Ratcliffe
authors.forename: Yajing
authors.initials: Y
authors.lastname: Rong
authors.forename: Andrew
authors.initials: A
authors.lastname: Roughton
authors.forename: Melanie
authors.initials: M
authors.lastname: Sammons
authors.forename: Robert
authors.initials: R
authors.lastname: Swanson
authors.forename: Heather
authors.initials: H
authors.lastname: Tracey
authors.forename: Glenn
authors.initials: G
authors.lastname: Walker
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D003511:Cyclohexanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006979:Hyperthermia, Induced; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D003511:Cyclohexanols; D007555:Isoxazoles; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat