Discovery of isoindoline and tetrahydroisoquinoline derivatives as potent, selective PPARδ agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 1; pp. 492 - 496
• Main Authors: Luckhurst, Christopher A., Stein, Linda A., Furber, Mark, Webb, Nicola, Ratcliffe, Marianne J., Allenby, Gary, Botterell, Sara, Tomlinson, Wendy, Martin, Barrie, Walding, Andrew
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.01.2011; Elsevier
• Subjects: agonists; beta oxidation; Binding Sites; Biological and medical sciences; biomarkers; Catalytic Domain; Computer Simulation; General and cellular metabolism. Vitamins; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Isoindolines; isozymes; Medical sciences; Pharmacology. Drug treatments; PPAR delta - agonists; PPAR delta - metabolism; PPARδ agonism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; pyruvate dehydrogenase (acetyl-transferring) kinase; Structure-Activity Relationship; Tetrahydroisoquinolines; Tetrahydroisoquinolines - chemical synthesis; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - pharmacology; PPARδ agonism; Isoindolines; Tetrahydroisoquinolines; Human; Agonist; Nuclear receptor; Isoquinoline derivatives; Enzyme; PPAR-β receptor; Transferases; Selectivity; Myotube; Acetic acid derivative; Isoindole derivatives; In vitro; Biological activity; Dose activity relation; Chlorine Organic compounds; Small molecule; [pyruvate dehydrogenase (acetyl-transferring)] kinase; Biological receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.10.117

We describe the discovery of small molecule isoindoline and tetrahydroisoquinoline derivatives as agonists of human peroxisome proliferator-activated receptor δ (PPARδ that displayed excellent selectivity over the PPARα and PPARγ subtypes. Compound 18 demonstrated efficacy in upregulation of PDK4 in human primary myotubes, a biomarker for increased fatty acid oxidation. 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.