1335218-34-2Relevant articles and documents
Development of 2-aminooxazoline 3-azaxanthene β-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D
Low, Jonathan D.,Bartberger, Michael D.,Chen, Kui,Cheng, Yuan,Fielden, Mark R.,Gore, Vijay,Hickman, Dean,Liu, Qingyian,Allen Sickmier,Vargas, Hugo M.,Werner, Jonathan,White, Ryan D.,Whittington, Douglas A.,Wood, Stephen,Minatti, Ana E.
, p. 1196 - 1206 (2017)
As part of an ongoing effort at Amgen to develop a disease-modifying therapy for Alzheimer's disease, we have previously used the aminooxazoline xanthene (AOX) scaffold to generate potent and orally efficacious BACE1 inhibitors. While AOX-BACE1 inhibitors demonstrated acceptable cardiovascular safety margins, a retinal pathological finding in rat toxicological studies demanded further investigation. It has been widely postulated that such retinal toxicity might be related to off-target inhibition of Cathepsin D (CatD), a closely related aspartyl protease. We report the development of AOX-BACE1 inhibitors with improved selectivity against CatD by following a structure- and property-based approach. Our efforts culminated in the discovery of a picolinamide-substituted 3-aza-AOX-BACE1 inhibitor absent of retinal effects in an early screening rat toxicology study.
Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease
Chen, Jian Jeffrey,Liu, Qingyian,Yuan, Chester,Gore, Vijay,Lopez, Patricia,Ma, Vu,Amegadzie, Albert,Qian, Wenyuan,Judd, Ted C.,Minatti, Ana E.,Brown, James,Cheng, Yuan,Xue, May,Zhong, Wenge,Dineen, Thomas A.,Epstein, Oleg,Human, Jason,Kreiman, Charles,Marx, Isaac,Weiss, Matthew M.,Hitchcock, Stephen A.,Powers, Timothy S.,Chen, Kui,Wen, Paul H.,Whittington, Douglas A.,Cheng, Alan C.,Bartberger, Michael D.,Hickman, Dean,Werner, Jonathan A.,Vargas, Hugo M.,Everds, Nancy E.,Vonderfecht, Steven L.,Dunn, Robert T.,Wood, Stephen,Fremeau, Robert T.,White, Ryan D.,Patel, Vinod F.
, p. 767 - 774 (2015)
The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthene
AMINO-OXAZINES AND AMINO-DIHYDROTHIAZINE COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE
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Page/Page column 79, (2013/04/10)
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, L, 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.
5-AMINO-OXAZEPINE AND 5-AMINO-THIAZEPANE COMPOUNDS AS BETA-SECRETASE ANTAGONISTS AND METHODS OF USE
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Page/Page column 52-53, (2012/08/28)
The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula (I); wherein variables A1, A3, A4, A5, A6, As, R2, R7, X and Y of Formula (I) are defined here
AMINO -DIHYDROOXAZINE AND AMINO - DIHYDROTHIAZINE SPIRO COMPOUNDS AS BETA - SECRETASE MODULATORS AND THEIR MEDICAL USE
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Page/Page column 55-56, (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).
