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 (Z)-fluoro-olefin amide bioisosteric replacement is an effective tool for addressing various shortcomings of the parent amide. In an effort to fine tune ADME properties of BACE1 preclinical candidate AM-6494, a series of structurally distinct (Z)-fluoro-olefin containing analogs was developed that culminated in compound 15. Herein, we detail design considerations, synthetic challenges, structure activity relationship (SAR) studies, and in vivo properties of an advanced compound in this novel series of BACE1 inhibitors. The development of a structurally distinct series of BACE1 inhibitors via the (Z)-fluoro-olefin amide bioisosteric replacement.,Frohn M, Liu L, Siegmund AC, Qian W, Amegadzie A, Chen N, Tan H, Hickman D, Wood S, Wen PH, Bartberger MD, Whittington DA, Allen JR, Bourbeau MP Bioorg Med Chem Lett. 2020 Jul 15;30(14):127240. doi: 10.1016/j.bmcl.2020.127240., Epub 2020 May 4. PMID:32527542[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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