Bioorganic and Medicinal Chemistry p. 714 - 733 (2012)
Update date:2022-07-30
Topics: Synthesis Carboxylic acid Design Acylsulfonamides Thiazolidinedione
Rikimaru, Kentaro
Wakabayashi, Takeshi
Abe, Hidenori
Imoto, Hiroshi
Maekawa, Tsuyoshi
Ujikawa, Osamu
Murase, Katsuhito
Matsuo, Takanori
Matsumoto, Mitsuharu
Nomura, Chisako
Tsuge, Hiroko
Arimura, Naoto
Kawakami, Kazutoshi
Sakamoto, Junichi
Funami, Miyuki
Mol, Clifford D.
Snell, Gyorgy P.
Bragstad, Kenneth A.
Sang, Bi-Ching
Dougan, Douglas R.
Tanaka, Toshimasa
Katayama, Nozomi
Horiguchi, Yoshiaki
Momose, Yu
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) γ agonists. Docking model analysis of in-house weak agonist 2 bound to the reported PPARγ 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.
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