Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar

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 IC 50 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.