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

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.

• Authors: Jonathan D Low, Michael D Bartberger, Kui Chen, Yuan Cheng, Mark R Fielden, Vijay Gore, Dean Hickman, Qingyian Liu, E Allen Sickmier, Hugo M Vargas, Jonathan Werner, Ryan D White, Douglas A Whittington, Stephen Wood, Ana E Minatti
• Journal: MedChemComm (Medchemcomm) Vol. 8 Issue 6 Pg. 1196-1206 (Jun 01 2017) ISSN: 2040-2503 [Print] England
• PMID: 30108829 (Publication Type: Journal Article)