Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents

Jennifer M Sealy; Anh P Truong; Luke Tso; Gary D Probst; Jose Aquino; Roy K Hom; Barbara M Jagodzinska; Darren Dressen; David W G Wone; Louis Brogley; Varghese John; Jay S Tung; Michael A Pleiss; John A Tucker; Andrei W Konradi; Michael S Dappen; Gergely Toth; Hu Pan; Lany Ruslim; Jim Miller; Michael P Bova; Sukanto Sinha; Kevin P Quinn; John-Michael Sauer

doi:10.1016/j.bmcl.2009.09.061

Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents

Bioorg Med Chem Lett. 2009 Nov 15;19(22):6386-91. doi: 10.1016/j.bmcl.2009.09.061. Epub 2009 Sep 19.

Affiliation

¹ Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

PMID: 19811916
DOI: 10.1016/j.bmcl.2009.09.061

Abstract

Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / chemistry
Amyloid Precursor Protein Secretases / genetics
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / chemistry
Aspartic Acid Endopeptidases / genetics
Drug Design*
Humans
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Substrate Specificity

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human