title: Modulation of PPAR receptor subtype selectivity of the ligands: aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety.
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.
authors.affiliation: Zydus Research Centre, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad, Gujarat 382210, India. pingalihk@rediffmail.com
authors.forename: Harikishore
authors.initials: H
authors.lastname: Pingali
authors.forename: Mukul
authors.initials: M
authors.lastname: Jain
authors.forename: Shailesh
authors.initials: S
authors.lastname: Shah
authors.forename: Pravin
authors.initials: P
authors.lastname: Patil
authors.forename: Pankaj
authors.initials: P
authors.lastname: Makadia
authors.forename: Pandurang
authors.initials: P
authors.lastname: Zaware
authors.forename: Kalapatapu V V M
authors.initials: KV
authors.lastname: Sairam
authors.forename: Jeevankumar
authors.initials: J
authors.lastname: Jamili
authors.forename: Ashish
authors.initials: A
authors.lastname: Goel
authors.forename: Megha
authors.initials: M
authors.lastname: Patel
authors.forename: Pankaj
authors.initials: P
authors.lastname: Patel
mesh_terms: D002087:Butyrates / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004146:Dioxanes / Q000737:chemistry; D015195:Drug Design; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D010080:Oxazoles / Q000737:chemistry; D047493:PPAR alpha / Q000737:chemistry* / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000737:chemistry*; D015533:Transcriptional Activation
chemical_list: C487401:2-methyl-c-5-(4-(5-methyl-2-(4-methylphenyl)-4-oxazolyl)butyl)-1,3-dioxane-r-2-carboxylic acid; D002087:Butyrates; D004146:Dioxanes; D008024:Ligands; D010080:Oxazoles; D047493:PPAR alpha; D047492:Peroxisome Proliferator-Activated Receptors; D006859:Hydrogen; D005998:Glycine; C500085:muraglitazar