Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064.
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.
Bass
Jonathan Y
JY
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
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
Parks
Derek J
DJ
Todd
Dan
D
Williams
Shawn P
SP
Wisely
G Bruce
GB
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
D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064