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 more ..
Target
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Description:
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)
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)
Categorized Comment
ChEMBL Assay Type: Functional
ChEMBL Assay Data Source: Scientific Literature
ChEMBL Target ID: 12227
ChEMBL target type: Target is a single protein chain
ChEMBL Assay Data Source: Scientific Literature
ChEMBL Target ID: 12227
ChEMBL target type: Target is a single protein chain
Result Definitions
| TID | Name | Description | Histogram | Type | Unit | |
|---|---|---|---|---|---|---|
| Outcome | The BioAssay activity outcome | Outcome | ||||
| 1 | EC50* | EC50 PubChem standard value |  | Float | μM | |
| 2 | EC50 activity comment | EC50 activity comment | String | |||
| 3 | EC50 standard flag | EC50 standard flag | | Integer | ||
| 4 | EC50 qualifier | EC50 qualifier | String | |||
| 5 | EC50 published value | EC50 published value | | Float | nM | |
| 6 | EC50 standard value | EC50 standard value | | Float | nM |
* Activity Concentration.
Data Table (Concise)
Classification
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