title: Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064.
abstract: Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: Jonathan Y
authors.initials: JY
authors.lastname: Bass
authors.forename: Richard D
authors.initials: RD
authors.lastname: Caldwell
authors.forename: Justin A
authors.initials: JA
authors.lastname: Caravella
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Creech
authors.forename: David N
authors.initials: DN
authors.lastname: Deaton
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Madauss
authors.forename: Harry B
authors.initials: HB
authors.lastname: Marr
authors.forename: Robert B
authors.initials: RB
authors.lastname: McFadyen
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Miller
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Dan
authors.initials: D
authors.lastname: Todd
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Williams
authors.forename: G Bruce
authors.initials: GB
authors.lastname: Wisely
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D031541:Fluorescence Resonance Energy Transfer; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064