Inhibitors of β-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718).

Research paper by Thomas A TA Dineen, Kui K Chen, Alan C AC Cheng, Katayoun K Derakhchan, Oleg O Epstein, Joel J Esmay, Dean D Hickman, Chuck E CE Kreiman, Isaac E IE Marx, Robert C RC Wahl, Paul H PH Wen, Matthew M MM Weiss, Douglas A DA Whittington, Stephen S Wood, Robert T RT Fremeau, et al.

Indexed on: 05 Nov '14Published on: 05 Nov '14Published in: Journal of Medicinal Chemistry


We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Aβ levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.

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