Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064.
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.
Akwabi-Ameyaw
Adwoa
A
Department of Medicinal Chemistry, GlaxoSmithKline, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA.
Bass
Jonathan Y
JY
Caldwell
Richard D
RD
Caravella
Justin A
JA
Chen
Lihong
L
Creech
Katrina L
KL
Deaton
David N
DN
Jones
Stacey A
SA
Kaldor
Istvan
I
Liu
Yaping
Y
Madauss
Kevin P
KP
Marr
Harry B
HB
McFadyen
Robert B
RB
Miller
Aaron B
AB
Navas
Frank
F
Parks
Derek J
DJ
Spearing
Paul K
PK
Todd
Dan
D
Williams
Shawn P
SP
Wisely
G Bruce
GB
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
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