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

• Published in: Journal of medicinal chemistry 2003-04, Vol.46 (8), p.1306-1317
• Main Authors: Ebdrup, Søren, Pettersson, Ingrid, Rasmussen, Hanne B, Deussen, Heinz-Josef, Frost Jensen, Anette, Mortensen, Steen B, Fleckner, Jan, Pridal, Lone, Nygaard, Lars, Sauerberg, Per
• Format: Article
• Language: English
• Subjects: Binding Sites; Biological and medical sciences; Crystallography, X-Ray; General and cellular metabolism. Vitamins; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Ligands; Medical sciences; Models, Molecular; Oxazines - chemical synthesis; Oxazines - chemistry; Oxazines - pharmacology; Pharmacology. Drug treatments; Phenylpropionates - chemical synthesis; Phenylpropionates - chemistry; Phenylpropionates - pharmacology; Radioligand Assay; Receptors, Cytoplasmic and Nuclear - agonists; Stereoisomerism; Transcription Factors - agonists
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm021027r

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.