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

Bioorg Med Chem. 2014 Mar 1;22(5):1782-90. doi: 10.1016/j.bmc.2014.01.003.

Shuanghua Hu ¹, Yazhong Huang ², Yong-Jin Wu ², Huan He ², Katherine A Grant-Young ², Robert L Bertekap ³, Valerie Whiterock ⁴, Patrick Brassil ⁴, Kimberley Lentz ⁴, Prasanna Sivaprakasam ⁵, David R Langley ⁵, Ryan S Westphal ³, Paul M Scola ²

Affiliations

1 Bristol-Myers Squibb Research and Development, Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: [email protected].
2 Bristol-Myers Squibb Research and Development, Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA.
3 Bristol-Myers Squibb Research and Development, Biology Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA.
4 Bristol-Myers Squibb Research and Development, Pharmaceutical Candidate Optimization, 5 Research Parkway, Wallingford, CT 06492, USA.
5 Bristol-Myers Squibb Research and Development, Computer Assisted Drug Design, 5 Research Parkway, Wallingford, CT 06492, USA.

PMID: 24495863 DOI: 10.1016/j.bmc.2014.01.003

Abstract

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.

Keywords

5-HT(6) antagonist; Alzheimer’s disease; Cognition; Feeding behavior; Obesity.

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