3u6a
Rational Design and Synthesis of Aminopiperazinones as Beta Secretase (BACE) Inhibitors
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 PubMedAminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets. Rational design and synthesis of aminopiperazinones as beta-secretase (BACE) inhibitors.,Tresadern G, Delgado F, Delgado O, Gijsen H, Macdonald GJ, Moechars D, Rombouts F, Alexander R, Spurlino J, Van Gool M, Vega JA, Trabanco AA Bioorg Med Chem Lett. 2011 Dec 15;21(24):7255-60. doi:, 10.1016/j.bmcl.2011.10.050. Epub 2011 Oct 20. PMID:22071305[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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