5UYU
Crystal structure of BACE1 in complex with 2-aminooxazoline-3-azaxanthene compound 12
Summary for 5UYU
| Entry DOI | 10.2210/pdb5uyu/pdb |
| Descriptor | Beta-secretase 1, IODIDE ION, (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-[5-(prop-1-yn-1-yl)pyridin-3-yl]-5'H-spiro[1-benzopyrano[2,3-c]pyridine-5,4'-[1,3]oxazol]-2'-amine, ... (5 entities in total) |
| Functional Keywords | aspartic protease, alzheimers disease, app, amyloid precursor protein, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 46999.55 |
| Authors | Whittington, D.A.,Long, A.M.,Sickmier, E.A. (deposition date: 2017-02-24, release date: 2017-05-17, Last modification date: 2024-11-13) |
| Primary citation | Low, J.D.,Bartberger, M.D.,Chen, K.,Cheng, Y.,Fielden, M.R.,Gore, V.,Hickman, D.,Liu, Q.,Allen Sickmier, E.,Vargas, H.M.,Werner, J.,White, R.D.,Whittington, D.A.,Wood, S.,Minatti, A.E. Development of 2-aminooxazoline 3-azaxanthene beta-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D. Medchemcomm, 8:1196-1206, 2017 Cited by PubMed Abstract: As part of an ongoing effort at Amgen to develop a disease-modifying therapy for Alzheimer's disease, we have previously used the aminooxazoline xanthene (AOX) scaffold to generate potent and orally efficacious BACE1 inhibitors. While AOX-BACE1 inhibitors demonstrated acceptable cardiovascular safety margins, a retinal pathological finding in rat toxicological studies demanded further investigation. It has been widely postulated that such retinal toxicity might be related to off-target inhibition of Cathepsin D (CatD), a closely related aspartyl protease. We report the development of AOX-BACE1 inhibitors with improved selectivity against CatD by following a structure- and property-based approach. Our efforts culminated in the discovery of a picolinamide-substituted 3-aza-AOX-BACE1 inhibitor absent of retinal effects in an early screening rat toxicology study. PubMed: 30108829DOI: 10.1039/c7md00106a PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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