Structure activity relationship studies of 3-arylsulfonyl-pyrido[1,2-a]pyrimidin-4-imines as potent 5-HT₆ antagonists.
Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2-a]pyrimidin-4-imine (1, IC50: 4.0 nM), as 5-HT6 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-HT6 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.
['Hu|Shuanghua|S|', 'Huang|Yazhong|Y|', 'Wu|Yong-Jin|YJ|', 'He|Huan|H|', 'Grant-Young|Katherine A|KA|', 'Bertekap|Robert L|RL|', 'Whiterock|Valerie|V|', 'Brassil|Patrick|P|', 'Lentz|Kimberley|K|', 'Sivaprakasam|Prasanna|P|', 'Langley|David R|DR|', 'Westphal|Ryan S|RS|', 'Scola|Paul M|PM|']
D000544:Alzheimer Disease D000818:Animals D006801:Humans D007097:Imines D062105:Molecular Docking Simulation D051381:Rats D011985:Receptors, Serotonin D013329:Structure-Activity Relationship
5-HT(6) antagonist Alzheimer’s disease Cognition Feeding behavior Obesity