Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation.

@article{Stauffer2007DiscoveryAS,
  title={Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation.},
  author={Shaun R. Stauffer and Matthew G Stanton and Alison R Gregro and Melissa A Steinbeiser and Jennifer R Shaffer and Philippe G. Nantermet and James C. Barrow and Kenneth E. Rittle and Dennis Collusi and Amy S. Espeseth and Ming-tain Lai and Beth Lynn Pietrak and M. Katharine Holloway and Georgia B. McGaughey and Sanjeev K Munshi and Jerome H. Hochman and Adam J. Simon and Harold G Selnick and Samuel Graham and Joseph P Vacca},
  journal={Bioorganic & medicinal chemistry letters},
  year={2007},
  volume={17 6},
  pages={1788-92}
}
A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux. 

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