4PZX

Synthesis, Characterization and PK/PD Studies of a Series of Spirocyclic Pyranochromene BACE1 Inhibitors

Summary for 4PZX

• Entry DOI: 10.2210/pdb4pzx/pdb
• Related: 4PZW
• Descriptor: Beta-secretase 1, NICKEL (II) ION, (4R,4a'R,10a'R)-7'-(5-chloropyridin-3-yl)-3',4',4a',10a'-tetrahydro-1'H-spiro[1,3-oxazole-4,5'-pyrano[3,4-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: 45875.63

Authors

Vigers, G.P.A. (deposition date: 2014-03-31, release date: 2014-05-14, Last modification date: 2014-10-15)

Primary citation

Volgraf, M.,Chan, L.,Huestis, M.P.,Purkey, H.E.,Burkard, M.,Geck Do, M.,Harris, J.,Hunt, K.W.,Liu, X.,Lyssikatos, J.P.,Rana, S.,Thomas, A.A.,Vigers, G.P.,Siu, M.
Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors.
Bioorg.Med.Chem.Lett., 24:2477-2480, 2014

PubMed Abstract: The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC50=110 nM) demonstrated a reduction in CSF Aβ in wild type rats after a single dose.

PubMed: 24780121
DOI: 10.1016/j.bmcl.2014.04.012

Experimental method

X-RAY DIFFRACTION (1.8 Å)