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Online ISSN: 1860-7187
March 11, 2011
VIP: Sulfonylthiadiazoles with an Unusual Binding Mode as Partial Dual Peroxisome Proliferator-Activated Receptor (PPAR) γ/δ Agonists with High Potency and in vivo Efficacy
Stefanie Keil,* Hans Matter, Karl Schönafinger, Maike Glien, Magali Mathieu, Jean-Pierre Marquette, Nadine Michot, Silke Haag-Diergarten, Matthias Urmann, Wolfgang Wendler
Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors that belong to the class of nuclear receptors. Compounds that simultaneously activate PPARγ and PPARδ subtypes are of potential interest to effectively target dyslipidemia and type II diabetes in a single pharmaceutically active molecule. In a multidisciplinary effort at Sanofi–Aventis, Stefanie Keil and fellow researchers identified a series of partial PPARδ and γ agonists with a novel chemical scaffold by high-throughput screening. The initial hit was further characterized by X-ray crystallography in complex with PPARδ. Surprisingly, this series of partial PPARγ/δ agonists reveals a new binding mode, which does not involve contact with the PPARδ activation helix AF-2. By effectively combining X-ray crystallography, structure-based design, medicinal chemistry, quantitative structure–activity relationship studies, and pharmacokinetics, it was possible to arrive at very potent compounds after lead optimization. The most promising molecule was shown to exhibit in vivo activity in chronic mice studies. Hence, these compounds may serve as valuable tools to further elucidate the complex roles of dual PPARγ/δ agonists for potential treatment of metabolic syndrome.
Received February 1, 2011; published online March 11, 2011, DOI: 10.1002/cmdc.201100047.