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

Christopher A Luckhurst; Linda A Stein; Mark Furber; Nicola Webb; Marianne J Ratcliffe; Gary Allenby; Sara Botterell; Wendy Tomlinson; Barrie Martin; Andrew Walding

doi:10.1016/j.bmcl.2010.10.117

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

Bioorg Med Chem Lett. 2011 Jan 1;21(1):492-6. doi: 10.1016/j.bmcl.2010.10.117. Epub 2010 Oct 27.

Authors

Christopher A Luckhurst¹, Linda A Stein, Mark Furber, Nicola Webb, Marianne J Ratcliffe, Gary Allenby, Sara Botterell, Wendy Tomlinson, Barrie Martin, Andrew Walding

Affiliation

¹ Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK. chris.luckhurst@astrazeneca.com

PMID: 21094606
DOI: 10.1016/j.bmcl.2010.10.117

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.

MeSH terms

Binding Sites
Catalytic Domain
Computer Simulation
Humans
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacology
PPAR delta / agonists*
PPAR delta / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Structure-Activity Relationship
Tetrahydroisoquinolines / chemical synthesis
Tetrahydroisoquinolines / chemistry*
Tetrahydroisoquinolines / pharmacology

Substances

Indoles
PDK4 protein, human
PPAR delta
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Tetrahydroisoquinolines
indoline
Protein Serine-Threonine Kinases