4di2
Crystal structure of BACE1 in complex with hydroxyethylamine inhibitor 37Crystal structure of BACE1 in complex with hydroxyethylamine inhibitor 37
Structural highlights
Publication Abstract from PubMedWe have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-beta peptide (Abeta) levels in wild-type rats following oral dosing. In this article, we describe further modifications of the P1-phenyl ring of the hydroxyethylamine series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate improved penetration into the CNS. Several of these compounds caused robust reduction of Abeta levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1. Design and Synthesis of Potent, Orally Efficacious Hydroxyethylamine Derived beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors.,Dineen TA, Weiss MM, Williamson T, Acton P, Babu-Khan S, Bartberger MD, Brown J, Chen K, Cheng Y, Citron M, Croghan MD, Dunn RT 2nd, Esmay J, Graceffa RF, Harried SS, Hickman D, Hitchcock SA, Horne DB, Huang H, Imbeah-Ampiah R, Judd T, Kaller MR, Kreiman CR, La DS, Li V, Lopez P, Louie S, Monenschein H, Nguyen TT, Pennington LD, San Miguel T, Sickmier EA, Vargas HM, Wahl RC, Wen PH, Whittington DA, Wood S, Xue Q, Yang BH, Patel VF, Zhong W J Med Chem. 2012 Apr 18. PMID:22468684[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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