Synthesis and Biological and Structural Characterization of the Dual-Acting Peroxisome Proliferator-Activated Receptor α/γ Agonist Ragaglitazar

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Abstract
A new and improved synthesis of the peroxisome proliferator-activated receptor (PPAR) agonist ragaglitazar applicable for large-scale preparation has been developed. The convergent synthetic procedure was based on a novel enzymatic kinetic resolution step. The conformation of ragaglitazar bound to the hPPARγ receptor was quite different compared to the single-crystal structures of the l-arginine salt of ragaglitazar. In particular, the phenoxazine ring system had varying orientations. Ragaglitazar had high affinity for the hPPARα and -γ receptors with IC50 values of 0.98 and 0.092 μM, respectively. The lack of hPPARδ activity could be explained by the absence of binding in the tail-up pocket in the hPPARδ receptor, in contrast to the hPPARδ agonist GW2433, which was able to bind in both the tail-up and tail-down pockets of the receptor.

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