3OOZ

Bace1 in complex with the aminohydantoin Compound 102

3OOZ の概要

• エントリーDOI: 10.2210/pdb3ooz/pdb
• 分子名称: Beta-secretase 1, (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(5-fluoropent-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (3 entities in total)
• 機能のキーワード: inhibitor, beta-secretase, protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P56817
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46874.38

構造登録者

Olland, A.M. (登録日: 2010-08-31, 公開日: 2011-08-31, 最終更新日: 2023-09-06)

主引用文献

Malamas, M.S.,Robichaud, A.,Erdei, J.,Quagliato, D.,Solvibile, W.,Zhou, P.,Morris, K.,Turner, J.,Wagner, E.,Fan, K.,Olland, A.,Jacobsen, S.,Reinhart, P.,Riddell, D.,Pangalos, M.
Design and Synthesis of Aminohydantoins as Potent and Selective Human beta-Secretase (BACE1) Inhibitors with Enhanced Brain Permeability
Bioorg.Med.Chem.Lett., 20:6597-6605, 2010

PubMed Abstract: The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogs exhibit good brain permeability (40-70%), low nanomolar potency for BACE1, and demonstrate >100-fold selectivity for the structurally related aspartyl proteases cathepsin D, renin and pepsin. Alkyl and alkoxy groups at the meta-position of the P1 phenyl, which extend toward the S3 region of the enzyme, have contributed to the ligand's reduced affinity for the efflux transporter protein P-gp, and decreased topological polar surface area, thus resulting in enhanced brain permeability. A fluorine substitution at the para-position of the P1 phenyl has contributed to 100-fold decrease of CYP3A4 inhibition and enhancement of compound metabolic stability. The plasma and brain protein binding properties of these new analogs are affected by substitutions at the P1 phenyl moiety. Higher compound protein binding was observed in the brain than in the plasma. Two structurally diverse potent BACE1 inhibitors (84 and 89) reduced 30% plasma Aβ40 in the Tg2576 mice in vivo model at 30 mg/kg p.o..

PubMed: 20880704
DOI: 10.1016/j.bmcl.2010.09.029

実験手法

X-RAY DIFFRACTION (1.8 Å)