4ybi | pdb_00004ybi
Crystal structure of BACE with amino thiazine inhibitor LY2811376
Structural highlights
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.[1] [2] Publication Abstract from PubMedAccording to the amyloid cascade hypothesis, cerebral deposition of amyloid-beta peptide (Abeta) is critical for Alzheimer's disease (AD) pathogenesis. Abeta generation is initiated when beta-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazi n-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Abeta-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Abeta reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Abeta reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man. Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor.,May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM, Stout SL, Timm DE, Smith Labell E, Gonzales CR, Nakano M, Jhee SS, Yen M, Ereshefsky L, Lindstrom TD, Calligaro DO, Cocke PJ, Greg Hall D, Friedrich S, Citron M, Audia JE J Neurosci. 2011 Nov 16;31(46):16507-16. doi: 10.1523/JNEUROSCI.3647-11.2011. PMID:22090477[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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