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• W2029042106 abstract "Alzheimer's disease (AD) is an incurable neurodegenerative disease for which current symptomatic therapies provide only modest benefit. A dramatic increase in the incidence of AD will occur by 2050 unless novel therapies, capable of slowing the underlying disease process, are approved. CNS accumulation of β-amyloid (Aβ40 and Aβ42) is recognized as fundamental in causing AD. Thus agents that prevent the synthesis and accumulation of brain Aβ should slow or halt AD progression. The CNS aspartyl protease BACE1 is the sole β-secretase in vivo for the proteolytic processing of APP to produce Aβ. Since BACE1 knockout mice make no Aβ and display a mild phenotype, small molecule BACE1 inhibitors are considered the best chronic amyloid lowering strategy for AD. As an intracellular CNS aspartyl protease, BACE1 was immediately recognized as a particularly challenging drug target. BACE1 inhibitors must possess good brain and cell penetration properties in order to access the intracellular acidic compartments of the neuron where BACE1 functions. Over a decade of effort on traditional peptidomimetic aspartyl protease inhibitor scaffolds, which lack the desirable properties of CNS drugs, has failed to produce viable BACE inhibitor drug candidates. Using a fragment-based NMR screening approach, a low affinity thioisourea hit was identified (BACE1 NMR Kd = 15 μM; BACE1-HTRF Ki = 100 μM). Protein-NMR, X-Ray analysis and medicinal chemistry efforts around this hit resulted in the discovery of a novel series of cyclic acylguanidine BACE inhibitors with μM affinity. Using a combination of traditional medicinal chemistry coupled with extensive use of CADD, X-ray crystallography and high throughput functional screening a series of iminohydantoin and iminopyrimidinone BACE inhibitors were identified. He we describe the in vitro pharmacological properties of low molecular weight, nonpeptidic, inhibitors at purified human BACE1 and in HEK-293 APPswe/lon expressing cells. Inhibitors possess high affinity BACE inhibition, Ki ∼6-50 nM with greater than 100-fold selectivity over related aspartyl proteases such as cathepsins D and E, pepsin and renin with the exception of the closely related BACE1 homolog, BACE2. These compounds are also potent inhibitors of BACE1-mediated processing of APP in cells with IC50s < 100 nM for inhibition of Aβ1-40, Aβ1-42 and sAPPβ synthesis." @default.
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• W2029042106 date "2010-07-01" @default.
• W2029042106 modified "2023-09-27" @default.
• W2029042106 title "P3-272: Pharmacological characterization of novel iminoheterocyclic BACE1 inhibitors for the treatment of Alzheimer's disease" @default.
• W2029042106 doi "https://doi.org/10.1016/j.jalz.2010.05.1772" @default.
• W2029042106 hasPublicationYear "2010" @default.
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