High affinity, bioavailable 3-amino-1,4-benzodiazepine-based gamma-secretase inhibitors

Andrew P Owens; Alan Nadin; Adam C Talbot; Earl E Clarke; Timothy Harrison; Huw D Lewis; Michael Reilly; Jonathan D J Wrigley; José L Castro

doi:10.1016/j.bmcl.2003.07.031

High affinity, bioavailable 3-amino-1,4-benzodiazepine-based gamma-secretase inhibitors

Bioorg Med Chem Lett. 2003 Nov 17;13(22):4143-5. doi: 10.1016/j.bmcl.2003.07.031.

Authors

Andrew P Owens¹, Alan Nadin, Adam C Talbot, Earl E Clarke, Timothy Harrison, Huw D Lewis, Michael Reilly, Jonathan D J Wrigley, José L Castro

Affiliation

¹ Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. andrew_owens@merck.com

PMID: 14592525
DOI: 10.1016/j.bmcl.2003.07.031

Abstract

In this paper, we describe the development of a novel series of high affinity, orally bioavailable 3-amino-1,4 benzodiazepine-based gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. We disclose structure-activity relationships based around the 1, 3 and 5 positions of the benzodiazepine core structure.

MeSH terms

Administration, Oral
Alzheimer Disease / drug therapy*
Amines / chemical synthesis
Amines / pharmacokinetics
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
Benzodiazepines / administration & dosage
Benzodiazepines / chemical synthesis*
Benzodiazepines / pharmacokinetics*
Benzodiazepines / pharmacology
Biological Availability
Biotransformation
Endopeptidases / metabolism*
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacokinetics*
Enzyme Inhibitors / pharmacology
Humans
Molecular Structure
Structure-Activity Relationship

Substances

Amines
Enzyme Inhibitors
Benzodiazepines
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
BACE1 protein, human