A new class of non-thiazolidinedione, non-carboxylic-acid-based highly selective peroxisome proliferator-activated receptor (PPAR) γ agonists: design and synthesis of benzylpyrazole acylsulfonamides.
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.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 17-85 Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Rikimaru_Kentarou@takeda.co.jp
Kentaro
K
Rikimaru
Takeshi
T
Wakabayashi
Hidenori
H
Abe
Hiroshi
H
Imoto
Tsuyoshi
T
Maekawa
Osamu
O
Ujikawa
Katsuhito
K
Murase
Takanori
T
Matsuo
Mitsuharu
M
Matsumoto
Chisako
C
Nomura
Hiroko
H
Tsuge
Naoto
N
Arimura
Kazutoshi
K
Kawakami
Junichi
J
Sakamoto
Miyuki
M
Funami
Clifford D
CD
Mol
Gyorgy P
GP
Snell
Kenneth A
KA
Bragstad
Bi-Ching
BC
Sang
Douglas R
DR
Dougan
Toshimasa
T
Tanaka
Nozomi
N
Katayama
Yoshiaki
Y
Horiguchi
Yu
Y
Momose
D000818:Animals; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry; D003198:Computer Simulation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000737:chemistry
D002264:Carboxylic Acids; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D011720:Pyrazoles; D013449:Sulfonamides; D045162:Thiazolidinediones; C031280:pyrazole