BACE-1 inhibition by a series of psi[CH2NH] reduced amide isosteres

Craig A Coburn; Shawn J Stachel; Kristen G Jones; Thomas G Steele; Diane M Rush; Jillian DiMuzio; Beth L Pietrak; Ming-Tain Lai; Qian Huang; Janet Lineberger; Lixia Jin; Sanjeev Munshi; M Katharine Holloway; Amy Espeseth; Adam Simon; Daria Hazuda; Samuel L Graham; Joseph P Vacca

doi:10.1016/j.bmcl.2006.04.076

BACE-1 inhibition by a series of psi[CH2NH] reduced amide isosteres

Bioorg Med Chem Lett. 2006 Jul 15;16(14):3635-8. doi: 10.1016/j.bmcl.2006.04.076. Epub 2006 May 11.

Authors

Craig A Coburn¹, Shawn J Stachel, Kristen G Jones, Thomas G Steele, Diane M Rush, Jillian DiMuzio, Beth L Pietrak, Ming-Tain Lai, Qian Huang, Janet Lineberger, Lixia Jin, Sanjeev Munshi, M Katharine Holloway, Amy Espeseth, Adam Simon, Daria Hazuda, Samuel L Graham, Joseph P Vacca

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. craig_coburn@merck.com

PMID: 16690314
DOI: 10.1016/j.bmcl.2006.04.076

Abstract

A series of beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a psi(CH2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.

MeSH terms

Amides / chemistry*
Amyloid Precursor Protein Secretases
Binding Sites
Endopeptidases / metabolism*
Immunoassay
Peptides / chemistry
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Amides
Peptides
Protease Inhibitors
Amyloid Precursor Protein Secretases
Endopeptidases