A novel series of potent gamma-secretase inhibitors based on a benzobicyclo[4.2.1]nonane core

Stephen J Lewis; Adrian L Smith; Joseph G Neduvelil; Graeme I Stevenson; Matthew J Lindon; A Brian Jones; Mark S Shearman; Dirk Beher; Earl Clarke; Jonathan D Best; James E Peachey; Timothy Harrison; J Luis Castro

doi:10.1016/j.bmcl.2004.10.062

A novel series of potent gamma-secretase inhibitors based on a benzobicyclo[4.2.1]nonane core

Bioorg Med Chem Lett. 2005 Jan 17;15(2):373-8. doi: 10.1016/j.bmcl.2004.10.062.

Authors

Stephen J Lewis¹, Adrian L Smith, Joseph G Neduvelil, Graeme I Stevenson, Matthew J Lindon, A Brian Jones, Mark S Shearman, Dirk Beher, Earl Clarke, Jonathan D Best, James E Peachey, Timothy Harrison, J Luis Castro

Affiliation

¹ Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. [email protected]

PMID: 15603957
DOI: 10.1016/j.bmcl.2004.10.062

Abstract

A new series of gamma-secretase inhibitors was developed from an in-house screening hit based on a benzobicyclo[4.2.1]nonane core. Lead optimisation studies led to the development of a series of potent inhibitors and in vivo efficacy was demonstrated.

MeSH terms

Alkanes / chemical synthesis*
Alkanes / pharmacology
Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Amides / chemistry
Amines / chemistry
Amyloid Precursor Protein Secretases
Animals
Aspartic Acid Endopeptidases
Brain / drug effects*
Brain / metabolism
Endopeptidases / metabolism*
Heterocyclic Compounds / chemistry*
Mice
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Alkanes
Amides
Amines
Heterocyclic Compounds
Protease Inhibitors
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
Bace1 protein, mouse
nonane