Discovery of isonicotinamide derived beta-secretase inhibitors: in vivo reduction of beta-amyloid.

Abstract

beta-Secretase inhibition offers an exciting opportunity for therapeutic intervention in the progression of Alzheimer's disease. A series of isonicotinamides derived from traditional aspartyl protease transition state isostere inhibitors has been optimized to yield low nanomolar inhibitors with sufficient penetration across the blood-brain barrier to demonstrate beta-amyloid lowering in a murine model.

• Authors: Matthew G Stanton, Shaun R Stauffer, Alison R Gregro, Melissa Steinbeiser, Philippe Nantermet, Sethu Sankaranarayanan, Eric A Price, Guoxin Wu, Ming-Chih Crouthamel, Joan Ellis, Ming-Tain Lai, Amy S Espeseth, Xiao-Ping Shi, Lixia Jin, Dennis Colussi, Beth Pietrak, Qian Huang, Min Xu, Adam J Simon, Samuel L Graham, Joseph P Vacca, Harold Selnick
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 15 Pg. 3431-3 (Jul 26 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17583334 (Publication Type: Journal Article)

Chemical References

• Amides
• Amyloid beta-Peptides
• Isonicotinic Acids
• Peptide Fragments
• amyloid beta-protein (1-40)
• Amyloid Precursor Protein Secretases

Topics

• Amides (chemical synthesis, chemistry, pharmacology)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors)
• Amyloid beta-Peptides (metabolism)
• Animals
• Biological Availability
• Brain (metabolism)
• Dose-Response Relationship, Drug
• Isonicotinic Acids (chemical synthesis, pharmacokinetics, pharmacology)
• Mice
• Peptide Fragments (metabolism)
• Rats
• Structure-Activity Relationship