6jt4

Crystal Structure of BACE1 in complex with N-{3-[(4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide

spinqualitylabelsall models 6jt4, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6jt4 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: C86, GOL, IOD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BACE1_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. Publication Abstract from PubMed The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as beta-secretase) is a promising target for the treatment of Alzheimer's disease. A pK(a) lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF(3) dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Abeta reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [(14) C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound. Trifluoromethyl Dihydrothiazine-Based beta-Secretase (BACE1) Inhibitors with Robust Central beta-Amyloid Reduction and Minimal Covalent Binding Burden.,Anan K, Iso Y, Oguma T, Nakahara K, Suzuki S, Yamamoto T, Matsuoka E, Ito H, Sakaguchi G, Ando S, Morimoto K, Kanegawa N, Kido Y, Kawachi T, Fukushima T, Teisman A, Urmaliya V, Dhuyvetter D, Borghys H, Austin N, Van Den Bergh A, Verboven P, Bischoff F, Gijsen HJM, Yamano Y, Kusakabe K ChemMedChem. 2019 Nov 20;14(22):1894-1910. doi: 10.1002/cmdc.201900478. Epub 2019 , Nov 12. PMID:31657130 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

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