Download MendeleySynthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar
Ebdrup, S., Pettersson, I., Rasmussen, H.B., Deussen, H.-J., Frost Jensen, A., Mortensen, S.B., Fleckner, J., Pridal, L., Nygaard, L., Sauerberg, P.(2003) J Med Chem 46: 1306-1317
- PubMed: 12672231
- DOI: https://doi.org/10.1021/jm021027r
- Primary Citation of Related Structures:
1NYX - PubMed 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 hPPARgamma 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 hPPARalpha and -gamma receptors with IC(50) values of 0.98 and 0.092 microM, respectively. The lack of hPPARdelta activity could be explained by the absence of binding in the tail-up pocket in the hPPARdelta receptor, in contrast to the hPPARdelta agonist GW2433, which was able to bind in both the tail-up and tail-down pockets of the receptor.
Organizational Affiliation:
Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark. sebd@novonordisk.com
