[4-(2H-1,2,3-Benzotriazol-2-yl)phenoxy]alkanoic Acids as Agonists of Peroxisome Proliferator-Activated Receptors (PPARs) by Anna Sparatore* a ), Cristina Godio b ), Elena Perrino a ), Sergio Romeo a ), Bart Staels c ), Jean-Charles Fruchart c ), and Maurizio Crestani b ) a )Istituto di Chimica Farmaceutica e Tossicologica, Universita ` di Milano, Viale Abruzzi 42, I-20131 Milan (phone: þ 390250317554; fax: þ 390250317565; e-mail: anna.sparatore@unimi.it) b ) Dipartimento di Scienze Farmacologiche, Universita ` di Milano, Via Balzaretti 9, I-20133 Milan c ) U545 Inserm, Departement d)Atherosclerose, Institut Pasteur de Lille and Faculte ´ de Pharmacie, Universite ´ de Lille 2, 1 rue du Prof. Calmette, F-59019 Lille Cedex A series of [4-(2H-1,2,3-benzotriazol-2-yl)phenoxy]alkanoic acids has been synthesized and tested as agonists of Peroxisome Proliferator-Activated Receptor (PPAR) a, g, and d. Three compounds displayed 56 to 96% of maximal activity of the reference drug Wy-14643 on PPARa,andtwoofthese, i.e. , 1 and 5, exhibited also moderate activity on either PPARg or d with efficacy equal to 50% and 46% of that of rosiglitazone and GW 501516, respectively. Thus, compounds 1 and 5 represent interesting starting point for preparing novel agents for the treatment of dyslipidemia or of dyslipidemic type-2 diabetes. 1.Introduction. – The Peroxisome Proliferator-Activated Receptors (PPARs) are a group of ligand-activated transcription factors that govern numerous biological processes, including energy metabolism (regulation of glucose and lipid metabolism), cell proliferation, skin development, and inflammation [1][2]. They are stimulated by long-chain saturated and polyunsaturated fatty acids and by icosanoids. Three different PPAR isotypes can be distinguished, namely, a, b/d, and g. PPARa is the most expressed at hepatic level; it regulates fatty acid oxidation, gluconeogenesis, and amino acid metabolism in the liver, and mediates the effects of fibrates [3–5], drugs used in the treatment of hyperlipidemia. PPARg is the most expressed in the adipose tissue where it regulates adipogenesis and is the target of the thiazolidinediones (glitazones) anti-diabetic drugs [6–9]. PPARb/d is ubiquitarious in adult mammal tissues, and its agonists increase HDL and lower hematic triglycerides [10]. Neither the fibrates nor the glitazones are able to lower simultaneously triglycerides and blood glucose, thus dual-acting PPARa/g agonists or, even better, PPAR pan- agonists are actively investigated for a better treatment of dyslipidemic type-2 diabetes (NIDDM) [11][12]. Indeed, there is a growing evidence of beneficial effects of fibrate treatment in NIDDM patients, and, therefore, non-selective but PPARa-preferring agonists are particularly pursued. Most PPAR agonists can be regarded as having three key regions: a) an acidic head (a thiazolidinedione ring or an alkanoyl residue), b) a linker part (a benzene ring bearing a variously functionalized chain in the para-position to the head), c)a hydrophobic tail (formed by a mono- or polycyclic aromatic or heteroaromatic moiety). Thus, to develop novel PPAR activators, we deemed worthy to explore the CHEMISTRY & BIODIVERSITY – Vol. 3 (2006) 385 # 2006 Verlag Helvetica Chimica Acta AG, Zürich