5UX4

Crystal Structure of Rat Cathepsin D with (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro- 7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3- c]pyridine-5,4'-[1,3]oxazol]-2'-amine

5UX4 の概要

• エントリーDOI: 10.2210/pdb5ux4/pdb
• 分子名称: Cathepsin D, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: cathepsin d, beta amyloid cleaving enzyme, bace1, hydrolase
• 由来する生物種: Rattus norvegicus (Rat)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 95635.91

構造登録者

Sickmier, A. (登録日: 2017-02-22, 公開日: 2018-06-13, 最終更新日: 2024-11-13)

主引用文献

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

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: 30108829
DOI: 10.1039/c7md00106a

実験手法

X-RAY DIFFRACTION (2.805 Å)