Discovery of a novel class of PPARdelta partial agonists.
Anthranilic acid GW9371 was identified as a novel class of PPARdelta partial agonist through high-throughput screening. The design and synthesis of SAR analogues is described. GSK1115 and GSK7227 show potent partial agonism of the PPARdelta target genes CPT1a and PDK4 in skeletal muscle cells.
Shearer
Barry G
BG
Department of Metabolic Chemistry, Metabolic Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA. barry.g.shearer@gsk.com
Patel
Hari S
HS
Billin
Andrew N
AN
Way
James M
JM
Winegar
Deborah A
DA
Lambert
Millard H
MH
Xu
Robert X
RX
Leesnitzer
Lisa M
LM
Merrihew
Raymond V
RV
Huet
Stephane
S
Willson
Timothy M
TM
D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006801:Humans; D015394:Molecular Structure; D047494:PPAR delta / Q000819:agonists*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
C531989:GSK1115; C531990:GSK7227; C531988:GW9371; D047494:PPAR delta; D044005:Tetrahydroisoquinolines; D062367:ortho-Aminobenzoates; D002334:Carnitine O-Palmitoyltransferase; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4