1. Optimization of N ′-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT 6 antagonistic binding pocket
- Author
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Josephus H. M. Lange, Remco Henzen, Natasja de Bruin, Jelle de Vries, Wouter I. Iwema Bakker, Wouter de Looff, Arnold P. den Hartog, Stefan Verhoog, Rob P. van de Woestijne, Chris G. Kruse, Arnold van Loevezijn, Jennifer Venhorst, and Martina A.W. van der Neut
- Subjects
0301 basic medicine ,Molecular model ,Stereochemistry ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,Pyrazoline ,Bioinformatics ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Humans ,Receptor ,Molecular Biology ,5-HT receptor ,Sulfonamides ,Binding Sites ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Antagonist ,Interaction site ,Molecular Docking Simulation ,030104 developmental biology ,Free fraction ,Receptors, Serotonin ,biology.protein ,Pyrazoles ,Molecular Medicine ,Serotonin Antagonists ,030217 neurology & neurosurgery - 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.
- Published
- 2016