Structure guided P1' modifications of HEA derived β-secretase inhibitors for the treatment of Alzheimer's disease

Holger Monenschein; Daniel B Horne; Michael D Bartberger; Stephen A Hitchcock; Thomas T Nguyen; Vinod F Patel; Lewis D Pennington; Wenge Zhong

doi:10.1016/j.bmcl.2012.04.060

Structure guided P1' modifications of HEA derived β-secretase inhibitors for the treatment of Alzheimer's disease

Bioorg Med Chem Lett. 2012 Jun 1;22(11):3607-11. doi: 10.1016/j.bmcl.2012.04.060. Epub 2012 Apr 19.

Authors

Holger Monenschein¹, Daniel B Horne, Michael D Bartberger, Stephen A Hitchcock, Thomas T Nguyen, Vinod F Patel, Lewis D Pennington, Wenge Zhong

Affiliation

¹ Envoy Therapeutics, 555 Heritage Drive, Jupiter, FL 33458, USA.

PMID: 22572583
DOI: 10.1016/j.bmcl.2012.04.060

Abstract

The synthesis and SAR of a series of BACE-1 hydroxyethyl amine inhibitors containing substitutions on a spirocyclobutyl moiety is described. Selectivity against cathepsin D, a related aspartyl protease with potential off target toxicity, and improved microsomal stability is exemplified.

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Binding Sites
Catalytic Domain
Cathepsin D / antagonists & inhibitors
Cathepsin D / metabolism
Computer Simulation
Ethylamines / chemical synthesis
Ethylamines / chemistry*
Ethylamines / therapeutic use
Humans
Microsomes, Liver / metabolism
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / therapeutic use
Structure-Activity Relationship

Substances

Ethylamines
Protease Inhibitors
Amyloid Precursor Protein Secretases
Cathepsin D
ethylamine