Design and Evaluation of Novel Biphenyl Sulfonamide Derivatives with Potent Histamine H3 Receptor Inverse Agonist Activity

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• 作者：Jonathan A. Covel ; Vincent J. Santora ; Jeffrey M. Smith ; Rena Hayashi ; Charlemagne Gallardo ; Michael I. Weinhouse ; Jason B. Ibarra ; Jeffrey A. Schultz ; Douglas M. Park ; Scott A. Estrada ; Brian J. Hofi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：September 24, 2009
• 年：2009
• 卷：52
• 期：18
• 页码：5603-5611
• 全文大小：806K
• 年卷期：v.52,no.18(September 24, 2009)
• ISSN：1520-4804

文摘

Antagonism of the histamine-H₃ receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H₃ receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-α-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.