4K8S

Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity

Summary for 4K8S

• Entry DOI: 10.2210/pdb4k8s/pdb
• Related: 4K9H 4KE0 4KE1
• Descriptor: Beta-secretase 1, (3S)-3-[(1R)-2-{[(4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]amino}-1-hydroxyethyl]-4-azabicyclo[11.3.1]heptadeca-1(17),13,15-trien-5-one (2 entities in total)
• Functional Keywords: protease, 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: 3
• Total formula weight: 131281.37

Authors

Jordan, S.R. (deposition date: 2013-04-18, release date: 2013-07-10, Last modification date: 2024-10-16)

Primary citation

Pennington, L.D.,Whittington, D.A.,Bartberger, M.D.,Jordan, S.R.,Monenschein, H.,Nguyen, T.T.,Yang, B.H.,Xue, Q.M.,Vounatsos, F.,Wahl, R.C.,Chen, K.,Wood, S.,Citron, M.,Patel, V.F.,Hitchcock, S.A.,Zhong, W.
Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity.
Bioorg.Med.Chem.Lett., 23:4459-4464, 2013

PubMed Abstract: We describe a systematic study of how macrocyclization in the P₁-P₃ region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.

PubMed: 23769639
DOI: 10.1016/j.bmcl.2013.05.028

Experimental method

X-RAY DIFFRACTION (2.39 Å)