6PZ4

co-crystal structure of BACE with inhibitor AM-6494

Summary for 6PZ4

• Entry DOI: 10.2210/pdb6pz4/pdb
• Descriptor: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: bace, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 46916.87

Authors

Huang, X. (deposition date: 2019-07-31, release date: 2019-10-23, Last modification date: 2024-10-09)

Primary citation

Pettus, L.H.,Bourbeau, M.P.,Bradley, J.,Bartberger, M.D.,Chen, K.,Hickman, D.,Johnson, M.,Liu, Q.,Manning, J.R.,Nanez, A.,Siegmund, A.C.,Wen, P.H.,Whittington, D.A.,Allen, J.R.,Wood, S.
Discovery of AM-6494: A Potent and Orally Efficacious beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor with in Vivo Selectivity over BACE2.
J.Med.Chem., 63:2263-2281, 2020

PubMed Abstract: β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid β (Aβ) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of , a molecule with biochemical IC BACE2/BACE1 ratio of 47. Administration of resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aβ levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, (AM-6494) was advanced to preclinical development.

PubMed: 31589043
DOI: 10.1021/acs.jmedchem.9b01034

Experimental method

X-RAY DIFFRACTION (1.85 Å)