4rcf | pdb_00004rcf
Crystal structure of BACE1 in complex with 2-aminooxazoline 4-fluoroxanthene inhibitor 49
Structural highlights
Function[BACE1_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 PubMedThe optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Abeta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Abeta reduction in a rat pharmacodynamic model (78% Abeta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo. Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors.,Epstein O, Bryan MC, Cheng AC, Derakhchan K, Dineen TA, Hickman D, Hua Z, Human JB, Kreiman C, Marx IE, Weiss MM, Wahl RC, Wen PH, Whittington DA, Wood S, Zheng XM, Fremeau RT Jr, White RD, Patel VF J Med Chem. 2014 Dec 11;57(23):9796-810. doi: 10.1021/jm501266w. Epub 2014 Nov, 12. PMID:25389560[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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