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 proteolytic enzyme beta-secretase (BACE1) plays a central role in the synthesis of the pathogenic beta-amyloid in Alzheimer's disease. SAR studies of the S2' region of the BACE1 ligand binding pocket with pyrazolyl and thienyl P2' side chains are reported. These analogs exhibit low nanomolar potency for BACE1, and demonstrate >50- to 100-fold selectivity for the structurally related aspartyl proteases BACE2 and cathepsin D. Small groups attached at the nitrogen of the P2' pyrazolyl moiety, together with the P3 pyrimidine nucleus projecting into the S3 region of the binding pocket, are critical components to ligand's potency and selectivity. P2' thiophene side chain analogs are highly potent BACE1 inhibitors with excellent selectivity against cathepsin D, but only modest selectivity against BACE2. The cell-based activity of these new analogs tracked well with their increased molecular binding with EC(50) values of 0.07-0.2muM in the ELISA assay for the most potent analogs. New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: Exploring the S2' region.,Malamas MS, Erdei J, Gunawan I, Barnes K, Hui Y, Johnson M, Robichaud A, Zhou P, Yan Y, Solvibile W, Turner J, Fan KY, Chopra R, Bard J, Pangalos MN Bioorg Med Chem Lett. 2011 Sep 15;21(18):5164-70. Epub 2011 Jul 23. PMID:21835615[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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