Title: A new class of non-thiazolidinedione, non-carboxylic-acid-based highly selective peroxisome proliferator-activated receptor (PPAR) ## agonists: design and synthesis of benzylpyrazole acylsulfonamides.

Abstract: Herein, we describe the design, synthesis, and structure-activity relationships of novel benzylpyrazole acylsulfonamides as non-thiazolidinedione (TZD), non-carboxylic-acid-based peroxisome proliferator-activated receptor (PPAR) ## agonists. Docking model analysis of in-house weak agonist 2 bound to the reported PPAR## ligand binding domain suggested that modification of the carboxylic acid of 2 would help strengthen the interaction of 2 with the TZD pocket and afford non-carboxylic-acid-based agonists. In this study, we used an acylsulfonamide group as the ring-opening analog of TZD as an isosteric replacement of carboxylic acid moiety of 2; further, preliminary modification of the terminal alkyl chain on the sulfonyl group gave the lead compound 3c. Subsequent optimization of the resulting compound gave the potent agonists 25c, 30b, and 30c with high metabolic stability and significant antidiabetic activity. Further, we have described the difference in binding mode of the carboxylic-acid-based agonist 1 and acylsulfonamide 3d.
(PMID: 22209730)

Putative Target:

ChEMBL Target ID: 102164
Target Type: SUBCELLULAR
Pref Name: Liver microsomes
Organism: Homo sapiens
Tax ID: 9606
Confidence: Target assigned is subcellular fraction
Relationship Type: Subcellular target assigned

ChEMBL Assay Type: ADMET

ChEMBL Assay Data Source: Scientific Literature

ChEMBL Assay Test Type: In vitro

ChEMBL Assay Tissue: Liver

ChEMBL Assay Subcellular Fraction: Microsomes