5CLM

1,4-Oxazine BACE1 inhibitors

Summary for 5CLM

• Entry DOI: 10.2210/pdb5clm/pdb
• Descriptor: Beta-secretase 1, N-{3-[(3R)-5-amino-3-methyl-3,6-dihydro-2H-1,4-oxazin-3-yl]phenyl}-5-chloropyridine-2-carboxamide, IODIDE ION, ... (5 entities in total)
• Functional Keywords: bace1 protease inhibitor, orally bioavailable, brain penetrant, proteros biostructures gmbh, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 45389.01

Authors

Rombouts, F.,Tresadern, G.,Delgado, O.,Martinez Lamenca, C.,Van Gool, M.,Garcia-Molina, A.,Alonso De Diego, S.,Oehlrich, D.,Prokopcova, H.,Alonso, J.M.,Austin, N.,Borghys, H.,Van Brandt, S.,Surkyn, M.,De Cleyn, M.,Vos, A.,Alexander, R.,MacDonald, G.,Moechars, D.,Trabanco, A.,Gijsen, H. (deposition date: 2015-07-16, release date: 2015-09-30, Last modification date: 2024-10-23)

Primary citation

Rombouts, F.J.,Tresadern, G.,Delgado, O.,Martinez-Lamenca, C.,Van Gool, M.,Garcia-Molina, A.,Alonso de Diego, S.A.,Oehlrich, D.,Prokopcova, H.,Alonso, J.M.,Austin, N.,Borghys, H.,Van Brandt, S.,Surkyn, M.,De Cleyn, M.,Vos, A.,Alexander, R.,Macdonald, G.,Moechars, D.,Gijsen, H.,Trabanco, A.A.
1,4-Oxazine beta-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.
J.Med.Chem., 58:8216-8235, 2015

PubMed Abstract: 1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.

PubMed: 26378740
DOI: 10.1021/acs.jmedchem.5b01101

Experimental method

X-RAY DIFFRACTION (2.61 Å)