Synthesis and structure-activity relationship studies of 1,3-disubstituted 2-propanols as BACE-1 inhibitors

Arun Babu Kumar; Jordan Micheal Anderson; Anthony Lester Melendez; Roman Manetsch

doi:10.1016/j.bmcl.2012.05.072

Synthesis and structure-activity relationship studies of 1,3-disubstituted 2-propanols as BACE-1 inhibitors

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4740-4. doi: 10.1016/j.bmcl.2012.05.072. Epub 2012 Jun 6.

Authors

Arun Babu Kumar¹, Jordan Micheal Anderson, Anthony Lester Melendez, Roman Manetsch

Affiliation

¹ Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Ave, Tampa, FL 33620, USA.

PMID: 22727644
DOI: 10.1016/j.bmcl.2012.05.072

Abstract

A library of 1,3-disubstituted 2-propanols was synthesized and evaluated as low molecular weight probes for β-secretase inhibition. By screening a library of 121 1,3-disubstituted 2-propanol derivatives, we identified few compounds inhibiting the enzyme at low micromolar concentrations. The initial hits were optimized to yield a potent BACE-1 inhibitor exhibiting an IC(50) constant in the nanomolar range. Exploration of the pharmacological properties revealed that these small molecular inhibitors possessed a high selectivity over cathepsin D and desirable physicochemical properties beneficial to cross the blood-brain barrier.

Publication types

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

MeSH terms

2-Propanol / chemical synthesis*
2-Propanol / metabolism
2-Propanol / pharmacology
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Blood-Brain Barrier / metabolism
Cathepsin D / antagonists & inhibitors
Chemical Phenomena
Molecular Structure
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / metabolism
Protease Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Protease Inhibitors
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
Cathepsin D
2-Propanol