2XYJ

Novel Sulfonylthiadiazoles with an Unusual Binding Mode as Partial Dual Peroxisome Proliferator-Activated Receptor (PPAR) gamma-delta Agonists with High Potency and In-vivo Efficacy

Summary for 2XYJ

• Entry DOI: 10.2210/pdb2xyj/pdb
• Related: 1GWX 1Y0S 2AWH 2B50 2BAW 2GWX 2J14 2XYW 2XYX 3GWX
• Descriptor: PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR DELTA, 5-CHLORO-2-METHOXY-N-[2-[4-[(5-PROPAN-2-YL-1,3,4-THIADIAZOL-2-YL)SULFAMOYL]PHENYL]ETHYL]BENZAMIDE, PENTAETHYLENE GLYCOL, ... (4 entities in total)
• Functional Keywords: transcription
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 68210.83

Authors

Marquette, J.-P.,Mathieu, M. (deposition date: 2010-11-18, release date: 2011-02-23, Last modification date: 2024-05-01)

Primary citation

Keil, S.,Matter, H.,Schonafinger, K.,Glien, M.,Mathieu, M.,Marquette, J.-P.,Michot, N.,Haag-Diergarten, S.,Urmann, M.,Wendler, W.
Sulfonylthiadiazoles with an Unusual Binding Mode as Partial Dual Peroxisome Proliferator-Activated Receptor (Ppar) Gamma / Delta Agonists with High Potency and in-Vivo Efficacy
Chemmedchem, 6:633-, 2011

PubMed Abstract: Compounds that simultaneously activate the peroxisome proliferator-activated receptor (PPAR) subtypes PPARγ and PPARδ have the potential to effectively target dyslipidemia and type II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ 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 PPARδ agonist; its optimization was based on the X-ray crystal structure in complex with PPARδ. In contrast to other PPARδ 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 PPARγ/δ agonists in the low nanomolar range were then identified. One of the most active members, compound 20 a, displayed EC₅₀ values of 1.6 and 336 nM for PPARδ and γ, respectively. The X-ray crystal structure of its complex with PPARδ confirms our design hypothesis. Compound 20 a 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 PPARγ agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPARγ/δ agonists for potential treatment of metabolic syndrome.

PubMed: 21400663
DOI: 10.1002/CMDC.201100047

Experimental method

X-RAY DIFFRACTION (2.3 Å)