Design and synthesis of potent and selective BACE-1 inhibitors

Catarina Björklund; Stefan Oscarson; Kurt Benkestock; Neera Borkakoti; Katarina Jansson; Jimmy Lindberg; Lotta Vrang; Anders Hallberg; Asa Rosenquist; Bertil Samuelsson

doi:10.1021/jm901168f

Design and synthesis of potent and selective BACE-1 inhibitors

J Med Chem. 2010 Feb 25;53(4):1458-64. doi: 10.1021/jm901168f.

Authors

Catarina Björklund¹, Stefan Oscarson, Kurt Benkestock, Neera Borkakoti, Katarina Jansson, Jimmy Lindberg, Lotta Vrang, Anders Hallberg, Asa Rosenquist, Bertil Samuelsson

Affiliation

¹ Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.

PMID: 20128595
DOI: 10.1021/jm901168f

Abstract

Highly potent BACE-1 protease inhibitors have been developed from an inhibitors containing a hydroxyethylene (HE) core displaying aryloxymethyl or benzyloxymethyl P1 side chain and a methoxy P1' side chain. The target molecules were synthesized in good overall yields from chiral carbohydrate starting materials. The inhibitors show high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnishes BACE-1 K(i) << 1 nM and displays >1000-fold selectivity over cathepsin D.

Publication types

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

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / chemistry
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / chemistry
Cathepsin D / antagonists & inhibitors
Crystallography, X-Ray
Drug Design
Ethylenes / chemical synthesis*
Ethylenes / chemistry
Ethylenes / pharmacology
Humans
Hydrogen Bonding
Models, Molecular
Stereoisomerism
Structure-Activity Relationship

Substances

Ethylenes
hydroxyethylene
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human
Cathepsin D

Associated data

PDB/3IXJ