FXR agonist activity of conformationally constrained analogs of GW 4064.
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Akwabi-Ameyaw
Adwoa
A
Department of Medicinal Chemistry, GlaxoSmithKline, 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
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
Bruce Wisely
G
G
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology; D009281:Naphthalenes / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000493:pharmacokinetics; D000099150:Receptor, Farnesoid X-Activated
D007555:Isoxazoles; D009281:Naphthalenes; D018160:Receptors, Cytoplasmic and Nuclear; D013876:Thiophenes; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064