Optimization of N'-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT sub(6) antagonistic binding pocket

The discovery of non-basic N'-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT sub(6) 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-HT sub(6) receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT sub(6) 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.