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.
Bristol-Myers Squibb Research and Development, Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: shuanghua.hu@bms.com.
Shuanghua
S
Hu
Bristol-Myers Squibb Research and Development, Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA.
Yazhong
Y
Huang
Bristol-Myers Squibb Research and Development, Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA.
Yong-Jin
YJ
Wu
Bristol-Myers Squibb Research and Development, Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA.
Huan
H
He
Bristol-Myers Squibb Research and Development, Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA.
Katherine A
KA
Grant-Young
Bristol-Myers Squibb Research and Development, Biology Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Robert L
RL
Bertekap
Bristol-Myers Squibb Research and Development, Pharmaceutical Candidate Optimization, 5 Research Parkway, Wallingford, CT 06492, USA.
Valerie
V
Whiterock
Bristol-Myers Squibb Research and Development, Pharmaceutical Candidate Optimization, 5 Research Parkway, Wallingford, CT 06492, USA.
Patrick
P
Brassil
Bristol-Myers Squibb Research and Development, Pharmaceutical Candidate Optimization, 5 Research Parkway, Wallingford, CT 06492, USA.
Kimberley
K
Lentz
Bristol-Myers Squibb Research and Development, Computer Assisted Drug Design, 5 Research Parkway, Wallingford, CT 06492, USA.
Prasanna
P
Sivaprakasam
Bristol-Myers Squibb Research and Development, Computer Assisted Drug Design, 5 Research Parkway, Wallingford, CT 06492, USA.
David R
DR
Langley
Bristol-Myers Squibb Research and Development, Biology Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
Ryan S
RS
Westphal
Bristol-Myers Squibb Research and Development, Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA.
Paul M
PM
Scola
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D006801:Humans; D007097:Imines / Q000493:pharmacokinetics* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D051381:Rats; D011985:Receptors, Serotonin / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D007097:Imines; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor
5-HT(6) antagonist; Alzheimer’s disease; Cognition; Feeding behavior; Obesity