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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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
Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists.
Bioorg Med Chem. 2011 Jan 15;19(2):771-82. doi: 10.1016/j.bmc.2010.12.023. Epub 2010 Dec 13.
- PubMed ID
- 21215640 [ View in PubMed]
- 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 PPARdelta 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Bezafibrate Peroxisome proliferator-activated receptor alpha EC 50 (nM) 42500 N/A N/A Details Bezafibrate Peroxisome proliferator-activated receptor delta EC 50 (nM) 18900 N/A N/A Details Bezafibrate Peroxisome proliferator-activated receptor gamma EC 50 (nM) 57200 N/A N/A Details Cardarine Peroxisome proliferator-activated receptor alpha EC 50 (nM) 1100 N/A N/A Details Cardarine Peroxisome proliferator-activated receptor delta EC 50 (nM) 1.2 N/A N/A Details