Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists.
To overcome the known liabilities of GW4064 a series of analogs were synthesized where the stilbene double bond is replaced by an oxymethylene or amino-methylene linker connecting a terminal benzoic acid with a substituted heteroaryl in the middle ring position. As a result we discovered compounds with increased potency in vitro that cause dose-dependent reduction of plasma triglycerides and cholesterol in db/db mice down to 2 x 1 mg/kg/day upon oral administration.
Abel
Ulrich
U
Phenex Pharmaceuticals AG, Waldhofer Strasse 104, 69123 Heidelberg, Germany.
Schlüter
Thomas
T
Schulz
Andreas
A
Hambruch
Eva
E
Steeneck
Christoph
C
Hornberger
Martin
M
Hoffmann
Thomas
T
Perović-Ottstadt
Sanja
S
Kinzel
Olaf
O
Burnet
Michael
M
Deuschle
Ulrich
U
Kremoser
Claus
C
D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002784:Cholesterol / Q000097:blood; D003198:Computer Simulation; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
D019440:Anti-Obesity Agents; D002784:Cholesterol; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064