5HU0
BACE1 in complex with 4-(3-(furan-2-carboxamido)phenyl)-1-methyl-5-oxo-4-phenylimidazolidin-2-iminium
Summary for 5HU0
| Entry DOI | 10.2210/pdb5hu0/pdb |
| Related | 5HTZ 5HU1 |
| Descriptor | Beta-secretase 1, L(+)-TARTARIC ACID, N-{3-[(2E,4R)-2-imino-1-methyl-5-oxo-4-phenylimidazolidin-4-yl]phenyl}furan-2-carboxamide, ... (4 entities in total) |
| Functional Keywords | alzheimer's, aspartyl protease, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Membrane; Single-pass type I membrane protein: P56817 |
| Total number of polymer chains | 2 |
| Total formula weight | 93008.12 |
| Authors | Orth, P. (deposition date: 2016-01-27, release date: 2016-11-09, Last modification date: 2024-10-30) |
| Primary citation | Scott, J.D.,Li, S.W.,Brunskill, A.P.,Chen, X.,Cox, K.,Cumming, J.N.,Forman, M.,Gilbert, E.J.,Hodgson, R.A.,Hyde, L.A.,Jiang, Q.,Iserloh, U.,Kazakevich, I.,Kuvelkar, R.,Mei, H.,Meredith, J.,Misiaszek, J.,Orth, P.,Rossiter, L.M.,Slater, M.,Stone, J.,Strickland, C.O.,Voigt, J.H.,Wang, G.,Wang, H.,Wu, Y.,Greenlee, W.J.,Parker, E.M.,Kennedy, M.E.,Stamford, A.W. Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease. J. Med. Chem., 59:10435-10450, 2016 Cited by PubMed Abstract: Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization. PubMed: 27933948DOI: 10.1021/acs.jmedchem.6b00307 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.83 Å) |
Structure validation
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