Synthesis and biological evaluation of phosphino dipeptide isostere inhibitor of human beta-secretase (BACE1)

Florian Manzenrieder; Andreas O Frank; Timo Huber; Cornelia Dorner-Ciossek; Horst Kessler

doi:10.1016/j.bmc.2007.03.072

Synthesis and biological evaluation of phosphino dipeptide isostere inhibitor of human beta-secretase (BACE1)

Bioorg Med Chem. 2007 Jun 15;15(12):4136-43. doi: 10.1016/j.bmc.2007.03.072. Epub 2007 Mar 30.

Authors

Florian Manzenrieder¹, Andreas O Frank, Timo Huber, Cornelia Dorner-Ciossek, Horst Kessler

Affiliation

¹ Department Chemie, Lehrstuhl II für Organische Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.

PMID: 17433698
DOI: 10.1016/j.bmc.2007.03.072

Abstract

Phosphino dipeptide (PDP) isosteres are known to be useful analogues of the transition state of metalloprotease substrates. Here we describe the use of this unit for the design of aspartic protease inhibitors. A PDP analogue of OM00-3, a potent BACE1 inhibitor, was synthesized and exhibited high biological activity (IC50 approximately 12 nM).

Publication types

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

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Chromatography, High Pressure Liquid
Dipeptides / chemical synthesis*
Dipeptides / chemistry
Dipeptides / pharmacology*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Magnetic Resonance Spectroscopy
Mass Spectrometry

Substances

Dipeptides
Enzyme Inhibitors
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human