2. Academic Validation
  3. Synthesis and structure-activity relationships of 2-aryl-4-oxazolylmethoxy benzylglycines and 2-aryl-4-thiazolylmethoxy benzylglycines as novel, potent PPARalpha selective activators- PPARalpha and PPARgamma selectivity modulation

Synthesis and structure-activity relationships of 2-aryl-4-oxazolylmethoxy benzylglycines and 2-aryl-4-thiazolylmethoxy benzylglycines as novel, potent PPARalpha selective activators- PPARalpha and PPARgamma selectivity modulation

  • Bioorg Med Chem Lett. 2010 May 1;20(9):2933-7. doi: 10.1016/j.bmcl.2010.03.019.
Xiang-Yang Ye 1,  Stephanie Chen,  Hao Zhang,  Kenneth T Locke,  Kevin O'Malley,  Litao Zhang,  Raijit Srivastava,  Bowman Miao,  Daniel Meyers,  Hossain Monshizadegan,  Debra Search,  Denise Grimm,  Rongan Zhang,  Jonathan Lippy,  Celeste Twamley,  Jodi K Muckelbauer,  Chiehying Chang,  Yongmi An,  Vinayak Hosagrahara,  Lisa Zhang,  T-J Yang,  Ranjan Mukherjee,  Peter T W Cheng,  Joseph A Tino
Affiliations

Affiliation

  • 1 Metabolic Diseases Chemistry, Bristol-Myers Squibb R&D, PO Box 5400, Princeton, NJ 08543-5400, USA. xiang-yang.ye@bms.com
PMID: 20356736 DOI: 10.1016/j.bmcl.2010.03.019
Abstract

The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARalpha/gamma dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARalpha versus PPARgamma. Potent, highly selective PPARalpha activators 2a and 2l, as well as PPARalpha activators with significant PPARgamma activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.

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