Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides.

Abstract

The evaluation of a series of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Aβ40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 μM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of β-amyloid peptides in mouse brain following oral dosing.

• Authors: Britt-Marie Swahn, Karin Kolmodin, Sofia Karlström, Stefan von Berg, Peter Söderman, Jörg Holenz, Stefan Berg, Johan Lindström, Marie Sundström, Dominika Turek, Jacob Kihlström, Can Slivo, Lars Andersson, David Pyring, Didier Rotticci, Liselotte Ohberg, Annika Kers, Krisztian Bogar, Fredrik von Kieseritzky, Margareta Bergh, Lise-Lotte Olsson, Juliette Janson, Susanna Eketjäll, Biljana Georgievska, Fredrik Jeppsson, Johanna Fälting
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 21 Pg. 9346-61 (Nov 08 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22924815 (Publication Type: Journal Article)

Chemical References

• AZD3839
• Alkynes
• Amides
• Amyloid beta-Peptides
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• Indoles
• KCNH2 protein, human
• Peptide Fragments
• Pyrimidines
• amyloid beta-protein (1-40)
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• BACE1 protein, human

Topics

• Administration, Oral
• Alkynes (chemical synthesis, pharmacokinetics, pharmacology)
• Amides (chemical synthesis, pharmacokinetics, pharmacology)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, chemistry)
• Amyloid beta-Peptides (metabolism)
• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors, chemistry)
• Biological Availability
• Brain (drug effects, metabolism)
• Cell Line
• Crystallography, X-Ray
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors)
• Female
• Fluorescence Resonance Energy Transfer
• Humans
• Hydrogen Bonding
• Indoles (chemical synthesis, pharmacokinetics, pharmacology)
• Mice
• Mice, Inbred C57BL
• Models, Molecular
• Molecular Structure
• Peptide Fragments (metabolism)
• Permeability
• Pyrimidines (chemical synthesis, pharmacokinetics, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship