5kr8
From Proteopedia
(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
Structural highlights
FunctionBACE1_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2] Publication Abstract from PubMedTruncation 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 Abeta 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. Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine beta-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors.,Wu YJ, Guernon J, Shi J, Marcin L, Higgins M, Rajamani R, Muckelbauer J, Lewis H, Chang C, Camac D, Toyn JH, Ahlijanian MK, Albright CF, Macor JE, Thompson LA J Med Chem. 2016 Sep 7. PMID:27559936[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
