4RRS

8-Tetrahydropyran-2-yl chromans: highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors

Summary for 4RRS

• Entry DOI: 10.2210/pdb4rrs/pdb
• Related: 4R5N 4RRN 4RRO
• Descriptor: Beta-secretase 1, NICKEL (II) ION, (4R,4a'R,10a'S)-8'-(2-fluoropyridin-3-yl)-4a'-methyl-3',4',4a',10a'-tetrahydro-2'H-spiro[1,3-oxazole-4,10'-pyrano[3,2-b]chromen]-2-amine, ... (4 entities in total)
• Functional Keywords: aspartyl protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 45873.20

Authors

Thomas, A.A.,Hunt, K.W.,Newhouse, B.,Watts, R.J.,Liu, X.,Vigers, G.P.A.,Smith, D.,Rhodes, S.P.,Brown, K.D.,Otten, J.N.,Burkard, M.,Cox, A.A.,Geck Do, M.K.,Dutcher, D.,Rana, S.,DeLisle, R.K.,Regal, K.,Wright, A.D.,Groneberg, R.,Liao, J.,Scearce-Levie, K.,Siu, M.,Purkey, H.E.,Lyssikatos, J.P. (deposition date: 2014-11-06, release date: 2014-12-03, Last modification date: 2024-10-30)

Primary citation

Thomas, A.A.,Hunt, K.W.,Newhouse, B.,Watts, R.J.,Liu, X.,Vigers, G.,Smith, D.,Rhodes, S.P.,Brown, K.D.,Otten, J.N.,Burkard, M.,Cox, A.A.,Geck Do, M.K.,Dutcher, D.,Rana, S.,DeLisle, R.K.,Regal, K.,Wright, A.D.,Groneberg, R.,Liao, J.,Scearce-Levie, K.,Siu, M.,Purkey, H.E.,Lyssikatos, J.P.
8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors.
J.Med.Chem., 57:10112-10129, 2014

PubMed Abstract: A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aβ1-40 at 60 mg/kg (PO).

PubMed: 25411915
DOI: 10.1021/jm5015132

Experimental method

X-RAY DIFFRACTION (1.8 Å)