title: Discovery of isoindoline and tetrahydroisoquinoline derivatives as potent, selective PPARδ agonists.
abstract: Small molecule isoindoline and tetrahydroisoquinoline derivatives have been identified as selective agonists of human peroxisome proliferator-activated receptor δ (PPARδ. Compound 18 demonstrated efficacy in a biomarker for increased fatty acid oxidation, with upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) in human primary myotubes.
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK. chris.luckhurst@astrazeneca.com
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Luckhurst
authors.forename: Linda A
authors.initials: LA
authors.lastname: Stein
authors.forename: Mark
authors.initials: M
authors.lastname: Furber
authors.forename: Nicola
authors.initials: N
authors.lastname: Webb
authors.forename: Marianne J
authors.initials: MJ
authors.lastname: Ratcliffe
authors.forename: Gary
authors.initials: G
authors.lastname: Allenby
authors.forename: Sara
authors.initials: S
authors.lastname: Botterell
authors.forename: Wendy
authors.initials: W
authors.lastname: Tomlinson
authors.forename: Barrie
authors.initials: B
authors.lastname: Martin
authors.forename: Andrew
authors.initials: A
authors.lastname: Walding
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D007211:Indoles; C000631432:PDK4 protein, human; D047494:PPAR delta; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D044005:Tetrahydroisoquinolines; C057812:indoline; D017346:Protein Serine-Threonine Kinases