2WF0

Human BACE-1 in complex with 4-ethyl-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((3-(trifluoromethyl)phenyl)methyl)amino)propyl)-8-(2-oxo-1-pyrrolidinyl)-6-quinolinecarboxamide

Summary for 2WF0

• Entry DOI: 10.2210/pdb2wf0/pdb
• Related: 1FKN 1M4H 1PY1 1SGZ 1TQF 1UJJ 1UJK 1W50 1W51 1XN2 1XN3 1XS7 1YM2 1YM4 2B8L 2B8V 2FDP 2VA5 2VA6 2VA7 2VIE 2VIJ 2VIY 2VIZ 2VJ6 2VJ7 2VJ9 2VKM 2VNM 2VNN 2WEZ 2WF1 2WF2 2WF3 2WF4
• Descriptor: BETA-SECRETASE 1, N-[(1S,2R)-1-BENZYL-2-HYDROXY-3-{[3-(TRIFLUOROMETHYL)BENZYL]AMINO}PROPYL]-4-ETHYL-8-(2-OXOPYRROLIDIN-1-YL)QUINOLINE-6-CARBOXAMIDE (3 entities in total)
• Functional Keywords: hydrolase, memapsin-2, polymorphism, glycoprotein, asp-2, bace-1, zymogen, protease, membrane, transmembrane, beta-secretase, disulfide bond, aspartyl protease, alternative splicing, beta-site app cleaving enzyme
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 44365.97

Authors

Charrier, N.,Clarke, B.,Cutler, L.,Demont, E.,Dingwall, C.,Dunsdon, R.,Hawkins, J.,Howes, C.,Hubbard, J.,Hussain, I.,Maile, G.,Matico, R.,Mosley, J.,Naylor, A.,O'Brien, A.,Redshaw, S.,Rowland, P.,Soleil, V.,Smith, K.J.,Sweitzer, S.,Theobald, P.,Vesey, D.,Walter, D.S.,Wayne, G. (deposition date: 2009-04-02, release date: 2009-05-19, Last modification date: 2024-11-20)

Primary citation

Charrier, N.,Clarke, B.,Cutler, L.,Demont, E.,Dingwall, C.,Dunsdon, R.,Hawkins, J.,Howes, C.,Hubbard, J.,Hussain, I.,Maile, G.,Matico, R.,Mosley, J.,Naylor, A.,O'Brien, A.,Redshaw, S.,Rowland, P.,Soleil, V.,Smith, K.J.,Sweitzer, S.,Theobald, P.,Vesey, D.,Walter, D.S.,Wayne, G.
Second Generation of Bace-1 Inhibitors. Part 1: The Need for Improved Pharmacokinetics.
Bioorg.Med.Chem.Lett., 19:3664-, 2009

PubMed Abstract: Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.

PubMed: 19428244
DOI: 10.1016/J.BMCL.2009.03.165

Experimental method

X-RAY DIFFRACTION (1.6 Å)