Modulation of PPAR receptor subtype selectivity of the ligands: aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety

  • Bioorg Med Chem Lett. 2008 Dec 15;18(24):6471-5. doi: 10.1016/j.bmcl.2008.10.062.
Harikishore Pingali  1 ,  Mukul Jain ,  Shailesh Shah ,  Pravin Patil ,  Pankaj Makadia ,  Pandurang Zaware ,  Kalapatapu V V M Sairam ,  Jeevankumar Jamili ,  Ashish Goel ,  Megha Patel ,  Pankaj Patel
Affiliations
  • 1. Zydus Research Centre, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad, Gujarat 382210, India. [email protected]
PMID: 18976908 DOI: 10.1016/j.bmcl.2008.10.062
Abstract

Oxazole containing glycine and oximinobutyric acid derivatives were synthesized as PPARalpha agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. Compound 13a was found to be a selective and potent PPARalpha agonist. Further 1,3-dioxane-2-carboxylic acid derivative 20 was synthesized by replacing the tetramethylene spacer of NS-220, a selective PPARalpha agonist with phenylene group and found to exhibit PPARalpha/gamma dual agonism. These results suggest that compounds possessing polymethylene spacer between pharmacophore and lipophilic tail exhibit predominantly PPARalpha agonism whereas those with an aromatic phenylene spacer shows PPARalpha/gamma dual agonism.