Synthesis and biological evaluation of N-alkylated 8-oxybenz[c]azepine derivatives as selective PPARδ agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 1; pp. 531 - 536
• Main Authors: Luckhurst, Christopher A., Ratcliffe, Marianne, Stein, Linda, Furber, Mark, Botterell, Sara, Laughton, David, Tomlinson, Wendy, Weaver, Richard, Chohan, Kamaldeep, Walding, Andrew
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.01.2011; Elsevier
• Subjects: agonists; Anilides - chemical synthesis; Anilides - chemistry; Anilides - pharmacokinetics; Animals; Benzazepine; Benzazepines - chemical synthesis; Benzazepines - chemistry; Benzazepines - pharmacokinetics; beta oxidation; Binding Sites; Biological and medical sciences; biomarkers; Computer Simulation; gene expression regulation; General and cellular metabolism. Vitamins; Hepatocytes - metabolism; Humans; isozymes; Medical sciences; messenger RNA; Microsomes, Liver - metabolism; Pharmacology. Drug treatments; PPAR alpha - agonists; PPAR alpha - metabolism; PPAR delta - agonists; PPAR delta - metabolism; PPAR gamma - agonists; PPAR gamma - metabolism; PPARδ agonism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; pyruvate dehydrogenase (acetyl-transferring) kinase; Rats; Up-Regulation; PPARδ agonism; Benzazepine; Agonist; Nuclear receptor; Intravenous administration; Rat; Benzazepine derivatives; PPAR-β receptor; Selectivity; Modeling; Dose activity relation; Chlorine Organic compounds; Molecular model; Chemical synthesis; Biological receptor; Human; Enzyme; Transferases; Rodentia; Myotube; Acetic acid derivative; In vitro; Biological activity; Vertebrata; Mammalia; Animal; Pharmacokinetics; [pyruvate dehydrogenase (acetyl-transferring)] kinase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.10.083

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. 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.