title: Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064.
abstract: Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA.
authors.forename: Adwoa
authors.initials: A
authors.lastname: Akwabi-Ameyaw
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: Stacey A
authors.initials: SA
authors.lastname: Jones
authors.forename: Istvan
authors.initials: I
authors.lastname: Kaldor
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
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: Frank
authors.initials: F
authors.lastname: Navas
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Paul K
authors.initials: PK
authors.lastname: Spearing
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: D000284:Administration, Oral; D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002779:Cholestasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000737:chemistry; D004195:Disease Models, Animal; D004285:Dogs; D005753:Gastric Mucosa / Q000378:metabolism; D000882:Haplorhini; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry; D013270:Stomach / Q000187:drug effects; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000737:chemistry; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002264:Carboxylic Acids; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D009281:Naphthalenes; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C085312:1-naphthoic acid; C412815:GW 4064