| 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
Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2' position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.
Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents.,Truong AP, Probst GD, Aquino J, Fang L, Brogley L, Sealy JM, Hom RK, Tucker JA, John V, Tung JS, Pleiss MA, Konradi AW, Sham HL, Dappen MS, Toth G, Yao N, Brecht E, Pan H, Artis DR, Ruslim L, Bova MP, Sinha S, Yednock TA, Zmolek W, Quinn KP, Sauer JM Bioorg Med Chem Lett. 2010 Aug 15;20(16):4789-94. Epub 2010 Jun 25. PMID:20634069[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
- ↑ Truong AP, Probst GD, Aquino J, Fang L, Brogley L, Sealy JM, Hom RK, Tucker JA, John V, Tung JS, Pleiss MA, Konradi AW, Sham HL, Dappen MS, Toth G, Yao N, Brecht E, Pan H, Artis DR, Ruslim L, Bova MP, Sinha S, Yednock TA, Zmolek W, Quinn KP, Sauer JM. Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents. Bioorg Med Chem Lett. 2010 Aug 15;20(16):4789-94. Epub 2010 Jun 25. PMID:20634069 doi:10.1016/j.bmcl.2010.06.112
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