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.