Optimization of N‿(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT₆ antagonistic binding pocket

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• 作者：Arnold van Loevezijn^&dagger ; ; ^&Dagger ; ; Jennifer Venhorst ; ^&dagger ; ; ^§ ; ; ^{jennifer.mccormack@tno.nl" class="auth_mail" title="E-mail the corresponding author} ; Wouter I. Iwema Bakker^¶ ; ; Jos H.M. Lange^‖ ; Wouter de Looff^&dagger ; &dagger ; ; Remco Henzen ; Jelle de Vries^&Dagger ; &Dagger ; ; Rob P. van de Woestijne ; Arnold P. den Hartog^§ ; § ; ; Stefan Verhoog^¶ ; ¶ ; ; Martina A.W. van der Neut^‖‖ ; Natasja M.W.J. de Bruin^&dagger ; &dagger ; &dagger ; ; Chris G. Kruse^&Dagger ; &Dagger ; &Dagger ;
• 关键词：5-HT6 receptor ; N&prime ; -(Arylsulfonyl)pyrazoline-1-carboxamidines ; Non-basic 5-HT6 antagonists ; Molecular modeling
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：26
• 期：6
• 页码：1605-1611
• 全文大小：4345 K

文摘

The discovery of non-basic N′-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT₆ antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT₆ receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT₆ antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies.