基于邻氧苄基甘氨酸的PPARα选择性激动剂BMS-711939的发现与临床前评估
Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist.
作者信息
Shi Yan, Li Jun, Kennedy Lawrence J, Tao Shiwei, Hernández Andrés S, Lai Zhi, Chen Sean, Wong Henry, Zhu Juliang, Trehan Ashok, Lim Ngiap-Kie, Zhang Huiping, Chen Bang-Chi, Locke Kenneth T, O'Malley Kevin M, Zhang Litao, Srivastava Rai Ajit, Miao Bowman, Meyers Daniel S, Monshizadegan Hossain, Search Debra, Grimm Denise, Zhang Rongan, Harrity Thomas, Kunselman Lori K, Cap Michael, Muckelbauer Jodi, Chang Chiehying, Krystek Stanley R, Li Yi-Xin, Hosagrahara Vinayak, Zhang Lisa, Kadiyala Pathanjali, Xu Carrie, Blanar Michael A, Zahler Robert, Mukherjee Ranjan, Cheng Peter T W, Tino Joseph A
机构信息
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
出版信息
ACS Med Chem Lett. 2016 Apr 4;7(6):590-4. doi: 10.1021/acsmedchemlett.6b00033. eCollection 2016 Jun 9.
BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 μM) and PPARδ (EC50 > 100 μM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.
BMS-711939（3）是一种强效且具有选择性的过氧化物酶体增殖物激活受体（PPAR）α激动剂，在PPAR-GAL4反式激活试验中，对人PPARα的半数有效浓度（EC50）为4 nM，与人PPARγ（EC50 = 4.5 μM）和PPARδ（EC50 > 100 μM）相比具有>1000倍的选择性。化合物3在临床前研究中还展现出优异的体内疗效和安全性，因此被选用于进一步的临床前评估。本文描述了3在临床前动物模型中的合成、构效关系（SAR）研究、体内药理学及其药代动力学性质。
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