title: Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Laboratoire GlaxoSmithKline, Centre de Recherches, 25-27 avenue du Québec, 91951 Les Ulis, France, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Sierra
authors.forename: Véronique
authors.initials: V
authors.lastname: Beneton
authors.forename: Anne-Bénédict
authors.initials: AB
authors.lastname: Boullay
authors.forename: Thierry
authors.initials: T
authors.lastname: Boyer
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Brewster
authors.forename: Frédéric
authors.initials: F
authors.lastname: Donche
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Forest
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Fouchet
authors.forename: Françoise J
authors.initials: FJ
authors.lastname: Gellibert
authors.forename: Didier A
authors.initials: DA
authors.lastname: Grillot
authors.forename: Millard H
authors.initials: MH
authors.lastname: Lambert
authors.forename: Alain
authors.initials: A
authors.lastname: Laroze
authors.forename: Christelle
authors.initials: C
authors.lastname: Le Grumelec
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Linget
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Montana
authors.forename: Van-Loc
authors.initials: VL
authors.lastname: Nguyen
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicodème
authors.forename: Vipul
authors.initials: V
authors.lastname: Patel
authors.forename: Annie
authors.initials: A
authors.lastname: Penfornis
authors.forename: Olivier
authors.initials: O
authors.lastname: Pineau
authors.forename: Danig
authors.initials: D
authors.lastname: Pohin
authors.forename: Florent
authors.initials: F
authors.lastname: Potvain
authors.forename: Géraldine
authors.initials: G
authors.lastname: Poulain
authors.forename: Cécile Bertho
authors.initials: CB
authors.lastname: Ruault
authors.forename: Michael
authors.initials: M
authors.lastname: Saunders
authors.forename: Jérôme
authors.initials: J
authors.lastname: Toum
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.forename: Robert X
authors.initials: RX
authors.lastname: Xu
authors.forename: Pascal M
authors.initials: PM
authors.lastname: Pianetti
mesh_terms: 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
chemical_list: 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