Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes

Hans G F Richter; Gregory M Benson; Denise Blum; Evelyne Chaput; Song Feng; Christophe Gardes; Uwe Grether; Peter Hartman; Bernd Kuhn; Rainer E Martin; Jean-Marc Plancher; Markus G Rudolph; Franz Schuler; Sven Taylor; Konrad H Bleicher

doi:10.1016/j.bmcl.2010.11.039

Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes

Bioorg Med Chem Lett. 2011 Jan 1;21(1):191-4. doi: 10.1016/j.bmcl.2010.11.039. Epub 2010 Nov 12.

Authors

Hans G F Richter¹, Gregory M Benson, Denise Blum, Evelyne Chaput, Song Feng, Christophe Gardes, Uwe Grether, Peter Hartman, Bernd Kuhn, Rainer E Martin, Jean-Marc Plancher, Markus G Rudolph, Franz Schuler, Sven Taylor, Konrad H Bleicher

Affiliation

¹ F Hoffmann-La Roche AG, Grenzacherstrasse, CH-4070 Basel, Switzerland.

PMID: 21134747
DOI: 10.1016/j.bmcl.2010.11.039

Abstract

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.

MeSH terms

Administration, Oral
Animals
Binding Sites
Computer Simulation
Diabetes Mellitus, Experimental / drug therapy
Drug Evaluation, Preclinical
Dyslipidemias / drug therapy
Hypoglycemic Agents / administration & dosage
Hypoglycemic Agents / chemistry*
Hypolipidemic Agents / administration & dosage
Hypolipidemic Agents / chemistry*
Mice
Mice, Knockout
Receptors, Cytoplasmic and Nuclear / agonists*
Receptors, Cytoplasmic and Nuclear / metabolism
Receptors, LDL / genetics
Receptors, LDL / metabolism
Structure-Activity Relationship

Substances

Hypoglycemic Agents
Hypolipidemic Agents
Receptors, Cytoplasmic and Nuclear
Receptors, LDL
farnesoid X-activated receptor