Novel heterocyclic scaffolds of GW4064 as farnesoid X receptor agonists

Terrence L Smalley Jr; Sharon Boggs; Justin A Caravella; Lihong Chen; Katrina L Creech; David N Deaton; Istvan Kaldor; Derek J Parks

doi:10.1016/j.bmcl.2014.11.050

Novel heterocyclic scaffolds of GW4064 as farnesoid X receptor agonists

Bioorg Med Chem Lett. 2015 Jan 15;25(2):280-4. doi: 10.1016/j.bmcl.2014.11.050. Epub 2014 Nov 26.

Authors

Terrence L Smalley Jr¹, Sharon Boggs², Justin A Caravella³, Lihong Chen⁴, Katrina L Creech⁵, David N Deaton², Istvan Kaldor², Derek J Parks⁵

Affiliations

¹ Muscle Metabolism DPU, Metabolic Pathways & Cardiovascular Discovery Performance Unit, GlaxoSmithKline, Inc., Five Moore Drive, Research Triangle Park, NC 27709, United States. Electronic address: terry.l.smalley@gsk.com.
² Muscle Metabolism DPU, Metabolic Pathways & Cardiovascular Discovery Performance Unit, GlaxoSmithKline, Inc., Five Moore Drive, Research Triangle Park, NC 27709, United States.
³ Computational and Structural Sciences, Platform Technology & Science, GlaxoSmithKline, Inc., Five Moore Drive, Research Triangle Park, NC 27709, United States.
⁴ Enteroendocrine DPU, Metabolic Pathways & Cardiovascular Discovery Performance Unit, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, United States.
⁵ Molecular Discovery Research, Platform Technology & Science, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, United States.

PMID: 25499883
DOI: 10.1016/j.bmcl.2014.11.050

Abstract

The farnesoid X receptor (FXR) may play a crucial role in a number of metabolic diseases and, as such, could potentially serve as a target for the development of therapeutics as a treatment for those diseases. Previous work has described GW4064 as an FXR agonist with an interesting activity profile. This manuscript will describe the synthesis of novel analogs of GW4064 and the activity profile of those analogs.

Keywords: FXR agonist; Heterocycles; Liver.

MeSH terms

Drug Evaluation, Preclinical
Fluorescence Resonance Energy Transfer
Humans
Isoxazoles / chemistry*
Isoxazoles / pharmacology*
Models, Molecular
Molecular Structure
Oxazolidinones / chemistry
Oxazolidinones / pharmacology*
Receptors, Cytoplasmic and Nuclear / agonists*
Structure-Activity Relationship

Substances

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