Loevezijn, A. vanA. vanLoevezijnVenhorst, J.J.VenhorstIwema Bakker, W.I.W.I.Iwema BakkerLange, J.H.M.J.H.M.LangeLooff, W. deW. deLooffHenzen, R.R.HenzenVries, J. deJ. deVriesWoestijne, R.P. van deR.P. van deWoestijneHartog, A.P. denA.P. denHartogVerhoog, S.S.VerhoogNeut, M.A.W. van derM.A.W. van derNeutBruin, N.M.W.J. deN.M.W.J. deBruinKruse, C.G.C.G.Kruse2022-03-052022-03-052016https://publica.fraunhofer.de/handle/publica/24464610.1016/j.bmcl.2016.02.001The 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.en540571572journal article