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

Bioorganic & Medicinal Chemistry Letters
Arnold van LoevezijnChris G Kruse

Abstract

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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Citations

Nov 6, 2020·Neuropsychiatric Disease and Treatment·Etsay Weldekidan TsegayZenawi Hagos Gufue
Jul 27, 2021·Bioorganic & Medicinal Chemistry Letters·Katarzyna Kucwaj-BryszJadwiga Handzlik

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