期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 20, 期 2, 页码 714-733出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.12.008
关键词
PPAR gamma agonist; Diabetes mellitus; SBDD; Acylsulfonamide; Isosteric replacement
资金
- Office of Science, Office of Basic Energy Science of the U.S. Department of Energy [DE-AC02-05CH11231]
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) gamma agonists. Docking model analysis of in-house weak agonist 2 bound to the reported PPAR gamma 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. (C) 2011 Published by Elsevier Ltd.
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