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

: 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.


Bioorganic & medicinal chemistry letters 26 (2016), No.6, pp.1605-1611
ISSN: 0960-894X
ISSN: 1464-3405
Journal Article
Fraunhofer IME ()

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.