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Development of 2-aminooxazoline 3-azaxanthene β-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D

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Abstract

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.

Graphical abstract: Development of 2-aminooxazoline 3-azaxanthene β-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D

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Publication details

The article was received on 28 Feb 2017, accepted on 20 Apr 2017 and first published on 27 Apr 2017


Article type: Research Article
DOI: 10.1039/C7MD00106A
Citation: Med. Chem. Commun., 2017, Advance Article
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    Development of 2-aminooxazoline 3-azaxanthene β-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D

    J. D. Low, M. D. Bartberger, K. Chen, Y. Cheng, M. R. Fielden, V. Gore, D. Hickman, Q. Liu, E. Allen Sickmier, H. M. Vargas, J. Werner, R. D. White, D. A. Whittington, S. Wood and A. E. Minatti, Med. Chem. Commun., 2017, Advance Article , DOI: 10.1039/C7MD00106A

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