Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists |
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Authors: | Makadia Pankaj Shah Shailesh R Pingali Harikishore Zaware Pandurang Patel Darshit Pola Suresh Thube Baban Priyadarshini Priyanka Suthar Dinesh Shah Maanan Giri Suresh Trivedi Chitrang Jain Mukul Patel Pankaj Bahekar Rajesh |
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Institution: | Zydus Research Centre, Moraiya, Ahmedabad, India. |
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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. |
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