Synthesis and Structure鈥揂ctivity Relationship Studies of O-Biphenyl-3-yl Carbamates as Peripherally Restricted Fatty Acid Amide Hydrolase Inhibitors

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• 作者：Guillermo Moreno-Sanz ; Andrea Duranti ; Laurin Melzig ; Claudio Fiorelli ; Gian Filippo Ruda ; Giampiero Colombano ; Paola Mestichelli ; Silvano Sanchini ; Andrea Tontini ; Marco Mor ; Tiziano Bandiera ; Rita Scarpelli ; Giorgio Tarzia ; Daniele Piomelli
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5917-5930
• 全文大小：480K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3鈥?carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB₁ cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure鈥揳ctivity relationships (SAR) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3鈥?carbamoyl-5-hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date.