Design and synthesis of substituted nicotinamides as inhibitors of soluble epoxide hydrolase

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• 作者：Steven J. Taylor ; Fariba Soleymanzadeh ; Anne B. Eldrup ; Neil A. Farrow ; Ingo Muegge ; Alison Kukulka ; Alisa K. Kabcenell ; Stephane De Lombaert
• 关键词：Soluble epoxide hydrolase ; Nicotinamides ; Epoxyeicosatrienoic acids ; Inhibitors
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：15 October 2009
• 年：2009
• 卷：19
• 期：20
• 页码：5864-5868
• 全文大小：763 K

文摘

A series of potent nicotinamide inhibitors of soluble epoxides hydrolase (sEH) is disclosed. This series was designed using structure-based deconstruction and a combination of two HTS hit series, resulting in hybrid analogs that retained the optimal potency from one series, and acceptable in vitro metabolic stability from the other. Structure-guided optimization of these analogs gave rise to nanomolar inhibitors of human sEH that had acceptable plasma exposure to qualify them as probes to determine the in vivo phenotypic consequences of sEH inhibition.