Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents.
The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.
Sierra
Michael L
ML
Department of Medicinal Chemistry, Laboratoire GlaxoSmithKline, Centre de Recherches, 25-27 avenue du Québec, 91951 Les Ulis, France, USA.
Beneton
Véronique
V
Boullay
Anne-Bénédict
AB
Boyer
Thierry
T
Brewster
Andrew G
AG
Donche
Frédéric
F
Forest
Marie-Claire
MC
Fouchet
Marie-Hélène
MH
Gellibert
Françoise J
FJ
Grillot
Didier A
DA
Lambert
Millard H
MH
Laroze
Alain
A
Le Grumelec
Christelle
C
Linget
Jean Michel
JM
Montana
Valerie G
VG
Nguyen
Van-Loc
VL
Nicodème
Edwige
E
Patel
Vipul
V
Penfornis
Annie
A
Pineau
Olivier
O
Pohin
Danig
D
Potvain
Florent
F
Poulain
Géraldine
G
Ruault
Cécile Bertho
CB
Saunders
Michael
M
Toum
Jérôme
J
Xu
H Eric
HE
Xu
Robert X
RX
Pianetti
Pascal M
PM
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood*; D015243:Cholesterol, VLDL / Q000097:blood; D018360:Crystallography, X-Ray; D004285:Dogs; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D047493:PPAR alpha / Q000819:agonists* / Q000737:chemistry; D011422:Propionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
C518308:2-methyl-2-(4-(((4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-ylcarbonyl)amino)methyl)phenoxy)propionic acid; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; D008024:Ligands; D047493:PPAR alpha; D011422:Propionates; D013844:Thiazoles; D014280:Triglycerides