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.
Keywords: 5-HT(6) receptor; Molecular modeling; Non-basic 5-HT(6) antagonists; N′-(Arylsulfonyl)pyrazoline-1-carboxamidines.
Copyright © 2016 Elsevier Ltd. All rights reserved.