Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes.
Herein we describe the synthesis and structure activity relationship of a new class of FXR agonists identified from a high-throughput screening campaign. Further optimization of the original hits led to molecules that were highly active in an LDL-receptor KO model for dyslipidemia. The most promising candidate is discussed in more detail.
F Hoffmann-La Roche AG, Grenzacherstrasse, CH-4070 Basel, Switzerland.
Hans G F
HG
Richter
Gregory M
GM
Benson
Denise
D
Blum
Evelyne
E
Chaput
Song
S
Feng
Christophe
C
Gardes
Uwe
U
Grether
Peter
P
Hartman
Bernd
B
Kuhn
Rainer E
RE
Martin
Jean-Marc
JM
Plancher
Markus G
MG
Rudolph
Franz
F
Schuler
Sven
S
Taylor
Konrad H
KH
Bleicher
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D050171:Dyslipidemias / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D000099150:Receptor, Farnesoid X-Activated