5KR8

(4~{S},6~{S})-4-[2,4-bis(fluoranyl)phenyl]-6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine (compound 5) bound to BACE1

Summary for 5KR8

• Entry DOI: 10.2210/pdb5kr8/pdb
• Related: 5KQF
• Descriptor: Beta-secretase 1, IODIDE ION, (4~{S},6~{S})-4-[2,4-bis(fluoranyl)phenyl]-6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-methyl-5,6-dihydro-1,3-thiazin-2-amine, ... (4 entities in total)
• Functional Keywords: bace-1, small molecule inhibitor, 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: 50684.78

Authors

Lewis, H.A.,Wu, Y.J.,Rajamani, R.,Thompson, L.A. (deposition date: 2016-07-07, release date: 2016-09-07, Last modification date: 2024-10-16)

Primary citation

Wu, Y.J.,Guernon, J.,Shi, J.,Marcin, L.,Higgins, M.,Rajamani, R.,Muckelbauer, J.,Lewis, H.,Chang, C.,Camac, D.,Toyn, J.H.,Ahlijanian, M.K.,Albright, C.F.,Macor, J.E.,Thompson, L.A.
Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine beta-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors.
J.Med.Chem., 59:8593-8600, 2016

PubMed Abstract: Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Aβ reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors.

PubMed: 27559936
DOI: 10.1021/acs.jmedchem.6b01012

Experimental method

X-RAY DIFFRACTION (2.118 Å)