Acridone-Based Inhibitors of Inosine 5'-Monophosphate Dehydrogenase: Discovery and SAR Leading to the Identification of N-(2-(6-(4-Ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2- fluoro-9-oxo-

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• 作者：Scott H. Watterson ; Ping Chen ; Yufen Zhao ; Henry H. Gu ; T. G. Murali Dhar ; Zili Xiao ; Shelley K. Ballentine ; Zhongqi Shen ; Catherine A. Fleener ; Katherine A. Rouleau ; Mary Obermeier ; Zheng Yang ; Kim W
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：July 26, 2007
• 年：2007
• 卷：50
• 期：15
• 页码：3730 - 3742
• 全文大小：206K
• 年卷期：v.50,no.15(July 26, 2007)
• ISSN：1520-4804

文摘

Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosinenucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH.The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus,development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile mayreduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discoveryand SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerabilitywhen administered orally in a rat adjuvant arthritis model.