2WF4

Human BACE-1 in complex with 6-ethyl-1-methyl-N-((1S)-2-oxo-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl)-1,3,4,6- tetrahydro(1,2)thiazepino(5,4,3-cd)indole-8-carboxamide 2,2-dioxide

Summary for 2WF4

• Entry DOI: 10.2210/pdb2wf4/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 2WF0 2WF1 2WF2 2WF3
• Descriptor: BETA-SECRETASE 1, N-[(1S)-1-BENZYL-2,2-DIHYDROXY-3-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)PROPYL]-6-ETHYL-1-METHYL-1,3,4,6-TETRAHYDRO[1,2]THIAZEPINO[5,4,3-CD]INDOLE-8-CARBOXAMIDE 2,2-DIOXIDE (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: 44332.01

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: 2009-05-12, Last modification date: 2024-11-13)

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 3: Towards Non Hydroxyethylamine Transition State Mimetics.
Bioorg.Med.Chem.Lett., 19:3674-, 2009

PubMed Abstract: Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.

PubMed: 19406640
DOI: 10.1016/J.BMCL.2009.03.149

Experimental method

X-RAY DIFFRACTION (1.8 Å)