Optimization of N'-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket.
Bioorganic & Medicinal Chemistry Letters(2016)
摘要
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.
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关键词
5-HT6 receptor,N′-(Arylsulfonyl)pyrazoline-1-carboxamidines,Non-basic 5-HT6 antagonists,Molecular modeling
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