title: Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists.
abstract: A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.
authors.affiliation: Zydus Research Centre, Moraiya, Ahmedabad, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Makadia
authors.forename: Shailesh R
authors.initials: SR
authors.lastname: Shah
authors.forename: Harikishore
authors.initials: H
authors.lastname: Pingali
authors.forename: Pandurang
authors.initials: P
authors.lastname: Zaware
authors.forename: Darshit
authors.initials: D
authors.lastname: Patel
authors.forename: Suresh
authors.initials: S
authors.lastname: Pola
authors.forename: Baban
authors.initials: B
authors.lastname: Thube
authors.forename: Priyanka
authors.initials: P
authors.lastname: Priyadarshini
authors.forename: Dinesh
authors.initials: D
authors.lastname: Suthar
authors.forename: Maanan
authors.initials: M
authors.lastname: Shah
authors.forename: Suresh
authors.initials: S
authors.lastname: Giri
authors.forename: Chitrang
authors.initials: C
authors.lastname: Trivedi
authors.forename: Mukul
authors.initials: M
authors.lastname: Jain
authors.forename: Pankaj
authors.initials: P
authors.lastname: Patel
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bahekar
mesh_terms: D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D004986:Ether / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008820:Mice, Obese; D010091:Oximes / Q000737:chemistry*; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry
chemical_list: C425931:GW 501516; D007004:Hypoglycemic Agents; D010091:Oximes; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D013844:Thiazoles; D004986:Ether