Synthesis, molecular modeling studies and biological evaluation of fluorine substituted analogs of GW 501516

Calin C Ciocoiu; Aina W Ravna; Ingebrigt Sylte; Arild C Rustan; Trond Vidar Hansen

doi:10.1016/j.bmc.2011.10.020

Synthesis, molecular modeling studies and biological evaluation of fluorine substituted analogs of GW 501516

Bioorg Med Chem. 2011 Dec 1;19(23):6982-8. doi: 10.1016/j.bmc.2011.10.020. Epub 2011 Oct 17.

Authors

Calin C Ciocoiu¹, Aina W Ravna, Ingebrigt Sylte, Arild C Rustan, Trond Vidar Hansen

Affiliation

¹ School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway.

PMID: 22051054
DOI: 10.1016/j.bmc.2011.10.020

Abstract

(±)-2-Fluoro-2-(2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)thio)phenoxy)acetic acid (2a) has been prepared and subjected to biological testing against all three subtypes of the PPARs. This compound exhibited agonist effects with EC(50) values of 560 and 55 nM against PPARα and PPARδ, respectively, in a luciferase assay. Moreover, compound (±)-2a also exhibited potent ability to induce oleic acid oxidation in a human myotube cell assay with EC(50)=3.7 nM. Compound (±)-2a can be classified as a dual PPARα/δ agonist with a 10-fold higher potency against the PPARδ receptor than against the PPARα receptor. Molecular modeling studies revealed that both enantiomers of 2a bind to the PPARδ receptor with similar binding energies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cells, Cultured
Humans
Hydrocarbons, Fluorinated / chemistry
Hydrocarbons, Fluorinated / pharmacology
Models, Molecular
Muscle Cells / drug effects
Muscle, Skeletal / cytology
Muscle, Skeletal / drug effects
PPAR alpha / agonists*
Protein Binding
Thiazoles / chemistry*
Thiazoles / pharmacology

Substances

GW 501516
Hydrocarbons, Fluorinated
PPAR alpha
Thiazoles