Identification of a subtype selective human PPARalpha agonist through parallel-array synthesis.
Using solid-phase, parallel-array synthesis, a series of urea-substituted thioisobutyric acids was synthesized and assayed for activity on the human PPAR subtypes. GW7647 (3) was identified as a potent human PPARalpha agonist with approximately 200-fold selectivity over PPARgamma and PPARdelta, and potent lipid-lowering activity in animal models of dyslipidemia. GW7647 (3) will be a valuable chemical tool for studying the biology of PPARalpha in human cells and animal models of disease.
Brown
P J
PJ
GlaxoSmithKline, Research Triangle Park, NC 27709-3398, USA. pjb5890@gsk.com
Stuart
L W
LW
Hurley
K P
KP
Lewis
M C
MC
Winegar
D A
DA
Wilson
J G
JG
Wilkison
W O
WO
Ittoop
O R
OR
Willson
T M
TM
D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D006224:Cricetinae; D004041:Dietary Fats / Q000494:pharmacology; D015195:Drug Design; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D014157:Transcription Factors / Q000819:agonists*
D002087:Butyrates; D004041:Dietary Fats; D000960:Hypolipidemic Agents; D010671:Phenylurea Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C121804:GW 9578