Design, Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPAR纬 Antagonists
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- 作者：Alice Asteian ; Anne-Laure Blayo ; Yuanjun He ; Marcel Koenig ; Youseung Shin ; Dana S. Kuruvilla ; Cesar A. Corzo ; Michael D. Cameron ; Li Lin ; Claudia Ruiz ; Susan Khan ; Naresh Kumar ; Scott Busby ; David P. Marciano ; Ruben D. Garcia-Ordonez ; Patrick R. Griffin ; Theodore M. Kamenecka
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2015
- 出版时间：September 10, 2015
- 年：2015
- 卷：6
- 期：9
- 页码：998-1003
- 全文大小：324K
- ISSN：1948-5875
文摘
The thiazolidinediones (TZD) typified by rosiglitazone are the only approved therapeutics targeting PPAR纬 for the treatment of type-2 diabetes (T2DM). Unfortunately, despite robust insulin sensitizing properties, they are accompanied by a number of severe side effects including congestive heart failure, edema, weight gain, and osteoporosis. We recently identified PPAR纬 antagonists that bind reversibly with high affinity but do not induce transactivation of the receptor, yet they act as insulin sensitizers in mouse models of diabetes (SR1664).1 This Letter details our synthetic exploration around this novel series of PPAR纬 antagonists based on an N-biphenylmethylindole scaffold. Structure鈥揳ctivity relationship studies led to the identification of compound 46 as a high affinity PPAR纬 antagonist that exhibits antidiabetic properties following oral administration in diet-induced obese mice.