1335218-45-5Relevant articles and documents
Lead optimization and modulation of hERG activity in a series of aminooxazoline xanthene β-site amyloid precursor protein cleaving enzyme (bace1) inhibitors
Epstein, Oleg,Bryan, Marian C.,Cheng, Alan C.,Derakhchan, Katayoun,Dineen, Thomas A.,Hickman, Dean,Hua, Zihao,Human, Jason B.,Kreiman, Charles,Marx, Isaac E.,Weiss, Matthew M.,Wahl, Robert C.,Wen, Paul H.,Whittington, Douglas A.,Wood, Stephen,Zheng, Xiao Mei,Fremeau, Robert T.,White, Ryan D.,Patel, Vinod F.
supporting information, p. 9796 - 9810 (2015/02/19)
The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2′ side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aβ reduction in a rat pharmacodynamic model (78% Aβ reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.
AMINO -DIHYDROOXAZINE AND AMINO - DIHYDROTHIAZINE SPIRO COMPOUNDS AS BETA - SECRETASE MODULATORS AND THEIR MEDICAL USE
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Page/Page column 61, (2011/10/10)
The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and related conditions. In one embodiment, the compounds have a general Formula (I): wherein A1, A2, A3, A4, A5, A6, R2, R7, X, Y and Z of Formula (I) are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairment, schizophrenia and other central nervous system conditions related to and/or caused by the formation and/or deposition of plaque on the brain. The invention also comprises further embodiments of Formula (I), intermediates and processes useful for the preparation of compounds of Formula (I).
