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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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Makadia P,Shah SR,Pingali H,Zaware P,Patel D,Pola S,Thube B,Priyadarshini P,Suthar D,Shah M,Giri S,Trivedi C,Jain M,Patel P,Bahekar R

doi

10.1016/j.bmc.2010.12.023

subject

Has Abstract

pub_date

2011-01-15 00:00:00

pages

771-82

issue

2

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(10)01114-4

journal_volume

19

pub_type

杂志文章

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