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

Autor:	Low JD; Department of Medicinal Chemistry , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA . Email: aminatti@amgen.com ; Tel: +1 805 447 4721., Bartberger MD; Department of Molecular Engineering , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA., Chen K; Department Discovery Technologies , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA., Cheng Y; Department of Medicinal Chemistry , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA . Email: aminatti@amgen.com ; Tel: +1 805 447 4721., Fielden MR; Comparative Biology and Safety Sciences , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA., Gore V; Department of Medicinal Chemistry , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA . Email: aminatti@amgen.com ; Tel: +1 805 447 4721., Hickman D; Department of Pharmacokinetics and Drug Metabolism , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA., Liu Q; Department of Medicinal Chemistry , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA . Email: aminatti@amgen.com ; Tel: +1 805 447 4721., Allen Sickmier E; Department of Molecular Engineering , Amgen Inc. , 360 Binney Street , Cambridge , MA 02142 , USA., Vargas HM; Comparative Biology and Safety Sciences , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA., Werner J; Comparative Biology and Safety Sciences , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA., White RD; Department of Medicinal Chemistry , Amgen Inc. , 360 Binney Street , Cambridge , MA 02142 , USA., Whittington DA; Department of Molecular Engineering , Amgen Inc. , 360 Binney Street , Cambridge , MA 02142 , USA., Wood S; Department of Neuroscience , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA., Minatti AE; Department of Medicinal Chemistry , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA . Email: aminatti@amgen.com ; Tel: +1 805 447 4721.
Jazyk:	angličtina
Zdroj:	MedChemComm [Medchemcomm] 2017 Apr 27; Vol. 8 (6), pp. 1196-1206. Date of Electronic Publication: 2017 Apr 27 (Print Publication: 2017).
DOI:	10.1039/c7md00106a
Abstrakt:	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.
Databáze:	MEDLINE
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