4B05

Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease

Summary for 4B05

• Entry DOI: 10.2210/pdb4b05/pdb
• Related: 1FKN 1M4H 1PY1 1SGZ 1TQF 1UJJ 1UJK 1W50 1W51 1XN2 1XN3 1XS7 1YM2 1YM4 2B8L 2B8V 2FDP 2VA5 2VA6 2VA7 2VIE 2VIJ 2VIY 2VIZ 2VJ6 2VJ7 2VJ9 2VKM 2VNM 2VNN 2WEZ 2WF0 2WF1 2WF2 2WF3 2WF4 2WJO 2XFI 2XFJ 2XFK 4ACU 4ACX 4AZY 4B00
• Descriptor: BETA-SECRETASE 1, ACETATE ION, SODIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase, aminoisoindole, alzheimer's disease
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 46572.07

Authors

Jeppsson, F.,Eketjall, S.,Janson, J.,Karlstrom, S.,Gustavsson, S.,Olsson, L.L.,Radesater, A.C.,Ploeger, B.,Cebers, G.,Kolmodin, K.,Swahn, B.M.,von Berg, S.,Bueters, T.,Falting, J. (deposition date: 2012-06-28, release date: 2012-10-17, Last modification date: 2024-10-23)

Primary citation

Jeppsson, F.,Eketjall, S.,Janson, J.,Karlstrom, S.,Gustavsson, S.,Olsson, L.L.,Radesater, A.C.,Ploeger, B.,Cebers, G.,Kolmodin, K.,Swahn, B.M.,von Berg, S.,Bueters, T.,Falting, J.
Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease.
J. Biol. Chem., 287:41245-41257, 2012

PubMed Abstract: β-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid β peptide (Aβ) species. Because cerebral deposition of Aβ species might be critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer (FRET) assay, Aβ and sAPPβ release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in mouse, guinea pig, and non-human primate. Pharmacokinetic/pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduces the levels of Aβ in brain, CSF, and plasma in several preclinical species. It might, therefore, have disease-modifying potential in the treatment of Alzheimer disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.

PubMed: 23048024
DOI: 10.1074/jbc.M112.409110

Experimental method

X-RAY DIFFRACTION (1.8 Å)