Bioorganic & Medicinal Chemistry Letters 2009-01-01

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

Steven J. Taylor, Fariba Soleymanzadeh, Anne B. Eldrup, Neil A. Farrow, Ingo Muegge, Alison Kukulka, Alisa K. Kabcenell, Stephane De Lombaert, Steven J. Taylor, Fariba Soleymanzadeh, Anne B. Eldrup, Neil A. Farrow, Ingo Muegge, Alison Kukulka, Alisa K. Kabcenell, Stephane De Lombaert

文献索引：Bioorg. Med. Chem. Lett. 19(20) , 5864-5868, (2009)

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摘要

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.