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  4. Optimization of N'-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket
 
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2016
Journal Article
Title

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

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.
Author(s)
Loevezijn, A. van
Venhorst, J.
Iwema Bakker, W.I.
Lange, J.H.M.
Looff, W. de
Henzen, R.
Vries, J. de
Woestijne, R.P. van de
Hartog, A.P. den
Verhoog, S.
Neut, M.A.W. van der
Bruin, N.M.W.J. de
Kruse, C.G.
Journal
Bioorganic & medicinal chemistry letters  
Open Access
DOI
10.1016/j.bmcl.2016.02.001
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