Synthesis and SAR of 1,2,3,4-tetrahydroisoquinolin-1-ones as novel G-protein-coupled receptor 40 (GPR40) antagonists.

@article{Humphries2009SynthesisAS,
  title={Synthesis and SAR of 1,2,3,4-tetrahydroisoquinolin-1-ones as novel G-protein-coupled receptor 40 (GPR40) antagonists.},
  author={Paul S Humphries and John Benbow and Paul D Bonin and David L Boyer and Shawn D. Doran and Richard K. Frisbie and David W Piotrowski and Gayatri Balan and Bruce M Bechle and Edward L. Conn and Kenneth J Dirico and R. M. Oliver and Walter C. Soeller and James A. Southers and Xiaojing Yang},
  journal={Bioorganic & medicinal chemistry letters},
  year={2009},
  volume={19 9},
  pages={2400-3}
}
The development of a series of novel 1,2,3,4-tetrahydroisoquinolin-1-ones as antagonists of G protein-coupled receptor 40 (GPR40) is described. The synthesis, in vitro inhibitory values for GPR40, in vitro microsomal clearance and rat in vivo clearance data are discussed. Initial hits displayed high rat in vivo clearances that were higher than liver blood flow. Optimization of rat in vivo clearance was achieved and led to the identification of 15i, whose rat oral pharmacokinetic data is… CONTINUE READING