title: Synthesis and biological evaluation of N-alkylated 8-oxybenz[c]azepine derivatives as selective PPARδ agonists.
abstract: We describe the discovery of small molecule benzazepine derivatives as agonists of human peroxisome proliferator-activated receptor δ (PPARδ) that displayed excellent selectivity over the PPARα and PPARγ subtypes. Compound 8 displayed good PK in the rat and efficacy in upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) mRNA in human primary myotubes, a biomarker for increased fatty acid oxidation.
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: Marianne
authors.initials: M
authors.lastname: Ratcliffe
authors.forename: Linda
authors.initials: L
authors.lastname: Stein
authors.forename: Mark
authors.initials: M
authors.lastname: Furber
authors.forename: Sara
authors.initials: S
authors.lastname: Botterell
authors.forename: David
authors.initials: D
authors.lastname: Laughton
authors.forename: Wendy
authors.initials: W
authors.lastname: Tomlinson
authors.forename: Richard
authors.initials: R
authors.lastname: Weaver
authors.forename: Kamaldeep
authors.initials: K
authors.lastname: Chohan
authors.forename: Andrew
authors.initials: A
authors.lastname: Walding
mesh_terms: D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D003198:Computer Simulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D015854:Up-Regulation
chemical_list: C557402:(2-(2-(1-(2,4-dichlorophenylamino)-1-oxobutan-2-yl)-2,3,4,5-tetrahydro-1H-benzo(c)azepin-8-yloxy)acetic acid); D000813:Anilides; D001552:Benzazepines; C000631432:PDK4 protein, human; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases