Structure- and property-based design of aminooxazoline xanthenes as selective, orally efficacious, and CNS penetrable BACE inhibitors for the treatment of Alzheimer's disease.

Abstract

A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human β-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS Aβ40 in naive rats.

• Authors: Hongbing Huang, Daniel S La, Alan C Cheng, Douglas A Whittington, Vinod F Patel, Kui Chen, Thomas A Dineen, Oleg Epstein, Russell Graceffa, Dean Hickman, Y-H Kiang, Steven Louie, Yi Luo, Robert C Wahl, Paul H Wen, Stephen Wood, Robert T Fremeau Jr
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 21 Pg. 9156-69 (Nov 08 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22928914 (Publication Type: Journal Article)

Chemical References

• Amyloid beta-Peptides
• Oxazoles
• Peptide Fragments
• Xanthenes
• amyloid beta-protein (1-40)
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• BACE1 protein, human

Topics

• Administration, Oral
• Alzheimer Disease (drug therapy)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors)
• Amyloid beta-Peptides (metabolism)
• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors)
• Brain (metabolism)
• Cell Line
• Crystallography, X-Ray
• Drug Design
• Humans
• Models, Molecular
• Molecular Structure
• Oxazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Peptide Fragments (metabolism)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship
• Xanthenes (chemical synthesis, pharmacokinetics, pharmacology)