| 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 PubMed
Genetic evidence points to deposition of amyloid-beta (Abeta) as a causal factor for Alzheimer's disease. Abeta generation is initiated when beta-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Abeta reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Abeta reduction of 80% at trough level.
Discovery of an Extremely Potent Thiazine-Based beta-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose.,Tadano G, Komano K, Yoshida S, Suzuki S, Nakahara K, Fuchino K, Fujimoto K, Matsuoka E, Yamamoto T, Asada N, Ito H, Sakaguchi G, Kanegawa N, Kido Y, Ando S, Fukushima T, Teisman A, Urmaliya V, Dhuyvetter D, Borghys H, Van Den Bergh A, Austin N, Gijsen HJM, Yamano Y, Iso Y, Kusakabe KI J Med Chem. 2019 Oct 24;62(20):9331-9337. doi: 10.1021/acs.jmedchem.9b01140. Epub, 2019 Oct 8. PMID:31549838[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
- ↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
- ↑ Tadano G, Komano K, Yoshida S, Suzuki S, Nakahara K, Fuchino K, Fujimoto K, Matsuoka E, Yamamoto T, Asada N, Ito H, Sakaguchi G, Kanegawa N, Kido Y, Ando S, Fukushima T, Teisman A, Urmaliya V, Dhuyvetter D, Borghys H, Van Den Bergh A, Austin N, Gijsen HJM, Yamano Y, Iso Y, Kusakabe KI. Discovery of an Extremely Potent Thiazine-Based beta-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose. J Med Chem. 2019 Oct 24;62(20):9331-9337. doi: 10.1021/acs.jmedchem.9b01140. Epub, 2019 Oct 8. PMID:31549838 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01140
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