Triazole-linked reduced amide isosteres: an approach for the fragment-based drug discovery of anti-Alzheimer's BACE1 inhibitors

Christopher J Monceaux; Chiho Hirata-Fukae; Polo C-H Lam; Maxim M Totrov; Yasuji Matsuoka; Paul R Carlier

doi:10.1016/j.bmcl.2011.05.007

Triazole-linked reduced amide isosteres: an approach for the fragment-based drug discovery of anti-Alzheimer's BACE1 inhibitors

Bioorg Med Chem Lett. 2011 Jul 1;21(13):3992-6. doi: 10.1016/j.bmcl.2011.05.007. Epub 2011 May 8.

Authors

Christopher J Monceaux¹, Chiho Hirata-Fukae, Polo C-H Lam, Maxim M Totrov, Yasuji Matsuoka, Paul R Carlier

Affiliation

¹ Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.

PMID: 21621412
DOI: 10.1016/j.bmcl.2011.05.007

Abstract

In the course of a β-site APP-cleaving enzyme 1 (BACE1) inhibitor discovery project an in situ synthesis/screening protocol was employed to prepare 120 triazole-linked reduced amide isostere inhibitors. Among these compounds, four showed modest (single digit micromolar) BACE1 inhibition. Our ligand design was based on a potent reduced amide isostere 1, wherein the P(2) amide moiety was replaced with an anti-1,2,3-triazole unit. Unfortunately, this replacement resulted in a 1000-fold decrease in potency. Docking studies of triazole-linked reduced amide isostere A3Z10 and potent oxadiazole-linked tertiary carbinamine 2a with BACE1 suggests that the docking poses of A3Z10 and 2a in the active sites are quite similar, with one exception. In the docked structures the placement of the protonated amine that engages D228 differs considerably between 2a and A3Z10. This difference could account for the lower BACE1 inhibition potency of A3Z10 and related compounds relative to 2a.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy*
Amides / chemical synthesis*
Amides / chemistry
Amides / therapeutic use
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Catalytic Domain
Drug Discovery*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / therapeutic use
Humans
Inhibitory Concentration 50
Models, Molecular
Molecular Structure
Oxidation-Reduction
Small Molecule Libraries
Triazoles / chemistry*

Substances

Amides
Enzyme Inhibitors
Small Molecule Libraries
Triazoles
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human