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

Article Details

Citation
Copy to clipboard

Ebdrup S, Pettersson I, Rasmussen HB, Deussen HJ, Frost Jensen A, Mortensen SB, Fleckner J, Pridal L, Nygaard L, Sauerberg P

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

J Med Chem. 2003 Apr 10;46(8):1306-17.

PubMed ID
12672231 [ View in 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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Peroxisome proliferator-activated receptor gammaP37231Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACIDPeroxisome proliferator-activated receptor gammaIC 50 (nM)92N/AN/ADetails
(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACIDPeroxisome proliferator-activated receptor gammaEC 50 (nM)600N/AN/ADetails
PioglitazonePeroxisome proliferator-activated receptor gammaIC 50 (nM)7400N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor alphaIC 50 (nM)>10000N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor gammaIC 50 (nM)440N/AN/ADetails
TesaglitazarPeroxisome proliferator-activated receptor alphaEC 50 (nM)1200N/AN/ADetails
TesaglitazarPeroxisome proliferator-activated receptor alphaIC 50 (nM)3800N/AN/ADetails
TesaglitazarPeroxisome proliferator-activated receptor gammaEC 50 (nM)1300N/AN/ADetails
TesaglitazarPeroxisome proliferator-activated receptor gammaIC 50 (nM)350N/AN/ADetails