Prolonged stability by cyclization: Macrocyclic phosphino dipeptide isostere inhibitors of beta-secretase (BACE1)

Timo Huber; Florian Manzenrieder; Christian A Kuttruff; Cornelia Dorner-Ciossek; Horst Kessler

doi:10.1016/j.bmcl.2009.05.053

Prolonged stability by cyclization: Macrocyclic phosphino dipeptide isostere inhibitors of beta-secretase (BACE1)

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4427-31. doi: 10.1016/j.bmcl.2009.05.053. Epub 2009 May 18.

Authors

Timo Huber¹, Florian Manzenrieder, Christian A Kuttruff, Cornelia Dorner-Ciossek, Horst Kessler

Affiliation

¹ Center of Integrated Protein Science at the Department Chemie and Institute for Advanced Study, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.

PMID: 19523824
DOI: 10.1016/j.bmcl.2009.05.053

Abstract

Cyclization of recently reported linear phosphino dipeptide isostere inhibitors of BACE1 via side chain olefin metathesis yielded macrocyclic BACE1 inhibitors. The most potent compound II-P1 (IC(50) of 47nM) and the corresponding linear analog I were tested for serum stability. The approach led to three times prolonged half life serum stability of 44min for the macrocyclic inhibitor II-P1 compared to the linear compound I.

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / chemistry
Amyloid Precursor Protein Secretases / metabolism
Animals
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / chemistry
Chemistry, Pharmaceutical / methods*
Dipeptides / chemistry
Drug Design
Humans
Inhibitory Concentration 50
Mice
Mice, Knockout
Models, Biological
Models, Chemical
Models, Molecular
Molecular Conformation
Peptides / chemistry
Phenotype
Time Factors

Substances

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