6od6
Structure of BACE-1 in complex with Ligand 13Structure of BACE-1 in complex with Ligand 13
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 PubMedDespite several years of research, only a handful of beta-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC(50) </= 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux. Evaluation of a Series of beta-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads.,Oehlrich D, Peschiulli A, Tresadern G, Van Gool M, Vega JA, De Lucas AI, Alonso de Diego SA, Prokopcova H, Austin N, Van Brandt S, Surkyn M, De Cleyn M, Vos A, Rombouts FJR, Macdonald G, Moechars D, Gijsen HJM, Trabanco AA ACS Med Chem Lett. 2019 Jul 2;10(8):1159-1165. doi: , 10.1021/acsmedchemlett.9b00181. eCollection 2019 Aug 8. PMID:31413800[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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