Macrocyclic peptidomimetic inhibitors of beta-secretase (BACE): first X-ray structure of a macrocyclic peptidomimetic-BACE complex

Isabel Rojo; José Alfredo Martín; Howard Broughton; David Timm; Jon Erickson; Hsiu-Chiung Yang; James R McCarthy

doi:10.1016/j.bmcl.2005.09.003

Macrocyclic peptidomimetic inhibitors of beta-secretase (BACE): first X-ray structure of a macrocyclic peptidomimetic-BACE complex

Bioorg Med Chem Lett. 2006 Jan 1;16(1):191-5. doi: 10.1016/j.bmcl.2005.09.003. Epub 2005 Oct 24.

Authors

Isabel Rojo¹, José Alfredo Martín, Howard Broughton, David Timm, Jon Erickson, Hsiu-Chiung Yang, James R McCarthy

Affiliation

¹ Lilly S.A., Avenida de la Industria 30, 28108 Alcobendas, Spain. irojo@lilly.com

PMID: 16249081
DOI: 10.1016/j.bmcl.2005.09.003

Abstract

The synthesis of novel macrocyclic peptidomimetic inhibitors of the enzyme BACE1 is described. These macrocycles are derived from a hydroxyethylene core structure. Compound 7 was co-crystallized with BACE1 and the X-ray structure of the complex elucidated at 1.6 Angstrom resolution. This molecule inhibits the production of the Abeta peptide in HEK293 cells overexpressing APP751sw.

MeSH terms

Alzheimer Disease / drug therapy
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor / chemistry
Animals
Aspartic Acid Endopeptidases
Cell Line
Chemistry, Pharmaceutical / methods*
Crystallography, X-Ray / methods*
Drug Design*
Endopeptidases / chemistry*
Endopeptidases / metabolism*
Humans
Kinetics
Models, Chemical
Models, Molecular
Protein Conformation
Protein Structure, Tertiary

Substances

Amyloid beta-Protein Precursor
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
BACE1 protein, human