FXR agonist activity of conformationally constrained analogs of GW 4064

Adwoa Akwabi-Ameyaw; Jonathan Y Bass; Richard D Caldwell; Justin A Caravella; Lihong Chen; Katrina L Creech; David N Deaton; Kevin P Madauss; Harry B Marr; Robert B McFadyen; Aaron B Miller; Frank Navas 3rd; Derek J Parks; Paul K Spearing; Dan Todd; Shawn P Williams; G Bruce Wisely

doi:10.1016/j.bmcl.2009.06.062

FXR agonist activity of conformationally constrained analogs of GW 4064

Bioorg Med Chem Lett. 2009 Aug 15;19(16):4733-9. doi: 10.1016/j.bmcl.2009.06.062. Epub 2009 Jun 21.

Authors

Adwoa Akwabi-Ameyaw¹, Jonathan Y Bass, Richard D Caldwell, Justin A Caravella, Lihong Chen, Katrina L Creech, David N Deaton, Kevin P Madauss, Harry B Marr, Robert B McFadyen, Aaron B Miller, Frank Navas 3rd, Derek J Parks, Paul K Spearing, Dan Todd, Shawn P Williams, G Bruce Wisely

Affiliation

¹ Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.

PMID: 19586769
DOI: 10.1016/j.bmcl.2009.06.062

Abstract

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.

MeSH terms

Animals
Binding Sites
Computer Simulation
Crystallography, X-Ray
Humans
Isoxazoles / chemistry*
Isoxazoles / pharmacology
Naphthalenes / chemistry*
Naphthalenes / pharmacokinetics
Rats
Receptors, Cytoplasmic and Nuclear / agonists*
Receptors, Cytoplasmic and Nuclear / metabolism
Structure-Activity Relationship
Thiophenes / chemistry*
Thiophenes / pharmacokinetics

Substances

Isoxazoles
Naphthalenes
Receptors, Cytoplasmic and Nuclear
Thiophenes
farnesoid X-activated receptor
GW 4064