| 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. | |
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MedLine Citation:
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PMID: 22209730 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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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Authors:
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Kentaro Rikimaru; Takeshi Wakabayashi; Hidenori Abe; Hiroshi Imoto; Tsuyoshi Maekawa; Osamu Ujikawa; Katsuhito Murase; Takanori Matsuo; Mitsuharu Matsumoto; Chisako Nomura; Hiroko Tsuge; Naoto Arimura; Kazutoshi Kawakami; Junichi Sakamoto; Miyuki Funami; Clifford D Mol; Gyorgy P Snell; Kenneth A Bragstad; Bi-Ching Sang; Douglas R Dougan; Toshimasa Tanaka; Nozomi Katayama; Yoshiaki Horiguchi; Yu Momose |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-13 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry Volume: - ISSN: 1464-3391 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2012-1-2 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9413298 Medline TA: Bioorg Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011. Published by Elsevier Ltd. |
Affiliation:
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Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 17-85 Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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