Structure activity relationship studies of 3-arylsulfonyl-pyrido[1,2-a]pyrimidin-4-imines as potent 5-HT6 antagonists

Abstract Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4 H -pyrido[1,2- a ]pyrimidin-4-imine ( 1 , IC 50 : 4.0 nM), as 5-HT 6 selective antagonists. Activity was improved some 2–4 fold when small, electron-donating groups were added to the central core as observed in 19 , 20 and 26 . Molecular docking of key compounds in a homology model of the human 5-HT 6 receptor was used to rationalize our structure–activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability.