Original article Synthesis and dual PPARa/d agonist effects of 1,4-disubstituted 1,2,3-triazole analogues of GW 501516 Calin C. Ciocoiu a , Nata  sa Nikoli  c b , Huyen Hoa Nguyen b , G. Hege Thoresen b , Arne J. Aasen a , Trond Vidar Hansen a, * a School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway b School of Pharmacy, Department of Pharmaceutical Biosciences, University of Oslo, PO BOX 1068, Blindern, N-0316 Oslo, Norway article info Article history: Received 2 November 2009 Received in revised form 23 March 2010 Accepted 23 March 2010 Available online 27 March 2010 Keywords: Triazoles GW 501516 Agonists PPARa PPARd Multiwell assay abstract Ten 1,4-disubstituted 1,2,3-triazoles 2ae2j were prepared and tested for their ability to increase oleic acid oxidation in human myotubes using a high-throughput multiwell assay. Compounds 2e (2-{4-[(1- (3-fluoro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid) and 2i (2-{4-[(1-(3-chloro-4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methyl- phenoxy}acetic acid) exhibited potent agonist activities. Compounds 2e and 2i also exhibited powerful agonist effects for both PPARa and PPARd in a luciferase-based assay. Consequently, these triazoles can be categorized as dual PPAR agonists. Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction The peroxisome proliferator-activated receptors (PPARa, PPARd and PPARg) belong to the nuclear receptor family of proteins and function as ligand-activated transcription factors [1]. These recep- tors play a key role in various tissues by controlling the expression of genes involved in lipid and carbohydrate metabolism. Agonists acting on the PPARs have been shown to have beneficial effects on lipid and glucose metabolism by decreasing triglyceride levels and increasing high density cholesterol level (HDL). Furthermore, PPAR agonists have the ability to improve glucose tolerance in type 2 diabetic patients [2]. Dyslipidemia and insulin resistance, two major components of the metabolic syndrome, have usually been treated with either the fibrate or the TZD classes of drugs that target PPARa and PPARg receptors, respectively [3,4]. In contrast, no drugs have been developed that target the PPARd and only a few selective and potent ligands that target this receptor have been identified [5]. The thiazole based compound GW 501516 (1)(Fig. 1) has been reported to be both highly potent and selective against the PPARd receptor [5a]. Interestingly, when obese rhesus monkeys were treated with GW 501516 (1) [5b], an increased level in the plasma HDL choles- terol as well as a decrease in the plasma triglyceride level was observed. Based on these observations, compound 1 is an inter- esting lead compound for the development of remedies against diabetes and the metabolic syndrome. Shen and coworkers repor- ted several PPARa/d dual agonists when the methyl-thiazole heterocycle in 1 was replaced with a 1,2,4-thiadiazole moiety [6]. Recently, a regioselective copper(I) catalyzed cycloaddition reac- tion between terminal alkynes and azides affording 1,4-disubsti- tuted 1,2,3-triazoles in high yields [7] was reported independently by the Sharpless and the Meldal groups. This reaction has found many applications [8]. For example,1,4-disubstituted 1,2,3-triazoles have recently been employed as mimics for amides [9] in combi- natorial chemistry library syntheses [10], in modifications of natural products [11] and in situ library screening [12]. Grimm’s bioisosteric rule [13] suggests bioisosteric substitution with tri- azoles should be five-membered heterocyclic rings such as the thiazole heterocyclic ring in GW 501516 (1) [14]. Furthermore, using our recently reported in vitro high-throughput multiwell assay method [15], fast access to measuring agonist effects in a whole cell-based system has become available to us. Since development of new agonists that target the PPARs is still of great interest within medicinal chemistry and drug discovery [16], we * Corresponding author. Tel.: þ47 22857450; fax: þ47 22855947. E-mail address: t.v.hansen@farmasi.uio.no (T.V. Hansen). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.03.035 European Journal of Medicinal Chemistry 45 (2010) 3047e3055