4wtu | pdb_00004wtu
Crystal structure of BACE1 in complex with 2-aminooxazoline 3-aza-4-fluoro-xanthene inhibitor 22
Structural highlights
FunctionBACE1_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2] Publication Abstract from PubMedBACE1 inhibition to prevent Abeta peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Abeta levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model. An Orally Available BACE1 Inhibitor That Affords Robust CNS Abeta Reduction without Cardiovascular Liabilities.,Cheng Y, Brown J, Judd TC, Lopez P, Qian W, Powers TS, Chen JJ, Bartberger MD, Chen K, Dunn RT 2nd, Epstein O, Fremeau RT Jr, Harried S, Hickman D, Hitchcock SA, Luo Y, Minatti AE, Patel VF, Vargas HM, Wahl RC, Weiss MM, Wen PH, White RD, Whittington DA, Zheng XM, Wood S ACS Med Chem Lett. 2014 Dec 29;6(2):210-5. doi: 10.1021/ml500458t. eCollection, 2015 Feb 12. PMID:25699151[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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