title: Discovery of potent, soluble and orally active TRPV1 antagonists. Structure-activity relationships of a series of isoxazoles.
abstract: Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.
authors: Merck Research Laboratories, MSD, Newhouse, Motherwell, Lanarkshire, UK. Paul.Ratcliffe@grunenthal.com
authors: Paul
authors: P
authors: Ratcliffe
authors: Lynn
authors: L
authors: Abernethy
authors: Nasrin
authors: N
authors: Ansari
authors: Ken
authors: K
authors: Cameron
authors: Tom
authors: T
authors: Clarkson
authors: Maureen
authors: M
authors: Dempster
authors: David
authors: D
authors: Dunn
authors: Anna-Marie
authors: AM
authors: Easson
authors: Darren
authors: D
authors: Edwards
authors: Katy
authors: K
authors: Everett
authors: Helen
authors: H
authors: Feilden
authors: Koc-Kan
authors: KK
authors: Ho
authors: Steve
authors: S
authors: Kultgen
authors: Peter
authors: P
authors: Littlewood
authors: John
authors: J
authors: Maclean
authors: Duncan
authors: D
authors: McArthur
authors: Deborah
authors: D
authors: McGregor
authors: Hazel
authors: H
authors: McLuskey
authors: Irina
authors: I
authors: Neagu
authors: Olaf
authors: O
authors: Nimz
authors: Lesley-Anne
authors: LA
authors: Nisbet
authors: Michael
authors: M
authors: Ohlmeyer
authors: Ronnie
authors: R
authors: Palin
authors: Quynhchi
authors: Q
authors: Pham
authors: Yajing
authors: Y
authors: Rong
authors: Andrew
authors: A
authors: Roughton
authors: Melanie
authors: M
authors: Sammons
authors: Robert
authors: R
authors: Swanson
authors: Heather
authors: H
authors: Tracey
authors: Glenn
authors: G
authors: Walker
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D002211:Capsaicin / Q000633:toxicity; D003511:Cyclohexanols / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007555:Isoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D003511:Cyclohexanols; D007555:Isoxazoles; D050916:TRPV Cation Channels; D002211:Capsaicin