Sulfonylthiadiazoles with an Unusual Binding Mode as Partial Dual Peroxisome Proliferator-Activated Receptor (PPAR) γ/δ Agonists with High Potency and in vivo Efficacy

Compounds that simultaneously activate the peroxisome proliferator-activated receptor (PPAR) subtypes PPAR gamma and PPAR delta have the potential to effectively target dyslipidemia and type II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPAR gamma agonists, such as edema and weight gain, are expected to be overcome by using partial instead of full agonists for this nuclear receptor family. Herein we report the discovery, synthesis, and optimization of a novel series of sulfonylthiadiazoles that are active as partial agonists. The initial compound 6 was discovered by high- throughput screening as a moderate partial PPARd agonist; its optimization was based on the X- ray crystal structure in complex with PPAR delta. In contrast to other PPARd agonists, this ligand does not interact directly with residues from the activation helix AF-2, which might be linked to its partial agonistic effect. Interestingly, the thiadiazole moiety fills a novel subpocket, which becomes accessible after moderate conformational rearrangement. The optimization was focused on introducing conformational constraints and replacing intramolecular hydrogen bonding interactions. Highly potent molecules with activity as dual partial PPAR gamma/delta agonists in the low nano-molar range were then identified. One of the most active members, compound 20a, displayed EC50 values of 1.6 and 336 nm for PPAR delta and gamma, respectively. The X-ray crystal structure of its complex with PPARd confirms our design hypothesis. Compound 20a clearly displayed in vivo activity in two chronic mice studies. Lipids were modified in a beneficial way in normolipidemic mice, and the development of overt diabetes could be prevented in pre-diabetic db/db mice. However, body weight gain was similar to that observed with the PPAR gamma agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPAR gamma/delta agonists for potential treatment of metabolic syndrome.