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Literature summary for 3.4.23.46 extracted from

  • Dineen, T.A.; Chen, K.; Cheng, A.C.; Derakhchan, K.; Epstein, O.; Esmay, J.; Hickman, D.; Kreiman, C.E.; Marx, I.E.; Wahl, R.C.; Wen, P.H.; Weiss, M.M.; Whittington, D.A.; Wood, S.; Fremeau, R.T.; White, R.D.; Patel, V.F.
    Inhibitors of ?-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5H-spiro[chromeno[2,3-b]pyridine-5,4-oxazol]-2-amine (AMG-8718) (2014), J. Med. Chem., 57, 9811-9831.
    View publication on PubMed
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Crystallization (Commentary)

Crystallization (Comment) Organism
in complex with inhibitor (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5H-spiro[chromeno[2,3-b]pyridine-5,4-oxazol]-2-amine. The aminooxazoline unit engages in hydrogen-bonding interactions with the catalytic aspartic acid residues of the enzyme, and the nitrogen atom of the 2-pyridyl-3-fluoro group interacts with Ser229 via a bridging water molecule in the S3 pocket Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(S)-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine inhibitor shows good BACE1 functional potency, permeability, intrinsic stability, and P-glycoprotein efflux ratios Homo sapiens
(S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5H-spiro[chromeno[2,3-b]pyridine-5,4-oxazol]-2-amine i.e. AMG-8718.compound exhibits a balanced profile of BACE1 potency, hERG binding affinity, and P-glycoprotein recognition. Compound produces robust and sustained reductions of cerebrospinal fluid and brain amyloid beta levels in a rat pharmacodynamic model Homo sapiens

Organism

Organism UniProt Comment Textmining
Homo sapiens P56817
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-

Source Tissue

Source Tissue Comment Organism Textmining
HEK-293 cell
-
 Homo sapiens
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IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0000007
-
 pH not specified in the publication, temperature not specified in the publication Homo sapiens (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5H-spiro[chromeno[2,3-b]pyridine-5,4-oxazol]-2-amine
0.0000009
-
 pH not specified in the publication, temperature not specified in the publication Homo sapiens (S)-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine