5ENK

Compound 18

Summary for 5ENK

• Entry DOI: 10.2210/pdb5enk/pdb
• Related: 5ENM
• Descriptor: Beta-secretase 1, GLYCEROL, IODIDE ION, ... (5 entities in total)
• Functional Keywords: bace, 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: 1
• Total formula weight: 50854.95

Authors

Lewis, H.A. (deposition date: 2015-11-09, release date: 2016-07-06, Last modification date: 2024-10-16)

Primary citation

Wu, Y.J.,Guernon, J.,Yang, F.,Snyder, L.,Shi, J.,Mcclure, A.,Rajamani, R.,Park, H.,Ng, A.,Lewis, H.,Chang, C.,Camac, D.,Toyn, J.H.,Ahlijanian, M.K.,Albright, C.F.,Macor, J.E.,Thompson, L.A.
Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain A beta Reduction in Rodents.
Acs Med.Chem.Lett., 7:271-276, 2016

PubMed Abstract: By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.

PubMed: 26985314
DOI: 10.1021/acsmedchemlett.5b00432

Experimental method

X-RAY DIFFRACTION (2.11 Å)