title: Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar.
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.
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark. sebd@novonordisk.com
authors.forename: Søren
authors.initials: S
authors.lastname: Ebdrup
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pettersson
authors.forename: Hanne B
authors.initials: HB
authors.lastname: Rasmussen
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Deussen
authors.forename: Anette
authors.initials: A
authors.lastname: Frost Jensen
authors.forename: Steen B
authors.initials: SB
authors.lastname: Mortensen
authors.forename: Jan
authors.initials: J
authors.lastname: Fleckner
authors.forename: Lone
authors.initials: L
authors.lastname: Pridal
authors.forename: Lars
authors.initials: L
authors.lastname: Nygaard
authors.forename: Per
authors.initials: P
authors.lastname: Sauerberg
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013237:Stereoisomerism; D014157:Transcription Factors / Q000819:agonists*
chemical_list: D007004:Hypoglycemic Agents; D008024:Ligands; D010078:Oxazines; D010666:Phenylpropionates; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C432703:ragaglitazar