6ej2 | pdb_00006ej2
BACE1 compound 28
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 PubMedBACE1 is responsible for the first step in APP proteolysis, leading to toxic Abeta production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles. Selective BACE1 inhibitors were found to exhibit two distinct conformational features proximal to the flap and the S3 subpocket. Several new molecules were designed and tested to make use of this observation. The combination of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in lead molecule 28, which exhibited approximately 50-fold selectivity. Compared to a nonselective BACE1/2 inhibitor, 28 showed significantly less inhibition of PMEL processing in human melanocytes, indicating good functional selectivity of this inhibitor class. Toward beta-Secretase-1 Inhibitors with Improved Isoform Selectivity.,Johansson P, Kaspersson K, Gurrell IK, Back E, Eketjall S, Scott CW, Cebers G, Thorne P, McKenzie MJ, Beaton H, Davey P, Kolmodin K, Holenz J, Duggan ME, Budd Haeberlein S, Burli RW J Med Chem. 2018 Apr 10. doi: 10.1021/acs.jmedchem.7b01716. PMID:29617572[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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