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

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 PPARα/γ 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 PPARα versus PPARγ. Potent, highly selective PPARα activators 2a and 2l, as well as PPARα activators with significant PPARγ 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.

Graphical abstractA series of potent, selective PPARα modulators incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy into oxybenzylglycine framework were designed and synthesized (structure shown as 2). The optimizations of R1, R2, and R3 in 2 have led to the identification of several potent, selective PPARα modulators such as 2a, 2l, and 2s. Their PK, in vivo pharmacology, and ADME profiles are discussed.Figure optionsDownload full-size imageDownload as PowerPoint slide