1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads

Rombouts, Frederik; Tresadern, Gary; Delgado, Oscar; Martínez-Lamenca, Carolina; Gool, Michiel Van; García-Molina, Aránzazu; Diego, Sergio A. Alonso de; Oehlrich, Daniel; Prokopcová, Hana; Alonso, J.M.; Austin, Nigel; Borghys, Herman; Brandt, Sven Van; Surkyn, Michel; Cleyn, Michel De; Vos, Ann; Alexander, Richard; Macdonald, Gregor; Moechars, Dieder; Gijsen, Harrie J. M.; Trabanco, Andrés A.

doi:10.1021/acs.jmedchem.5b01101

Cited by 70 publications

(79 citation statements)

References 30 publications

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“…Finally, only two hits were confirmed in all three assays: 13 and 14 . However, 14 is an intermediate from a BACE1 medicinal chemistry exploration, 23 whereas 13 is a structurally related but much weaker binding compound synthesized for an unrelated project. For fragments 13 and 14 , K D ’s of respectively 0.83 and 0.12 mM could be calculated from the TF CR data.…”

Section: Resultsmentioning

confidence: 99%

“…23 Instead, the quinazoline occupies the S1 pocket and the dimethylamine is oriented toward S3. Fragment 12 forms an H-bond between the protonated quinazoline and the backbone carbonyl of Phe108 in two of the three copies of BACE1 and forms π-stacking and hydrophobic interactions with residues Leu30, Tyr71, Phe108, Ile110, Trp115, and Ile118 (Figure 7B).…”

Section: Resultsmentioning

confidence: 99%

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Fragment Binding to β-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches

et al. 2017

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An approach to identify β-secretase 1 (BACE1) fragment binders that do not interact with the catalytic aspartate dyad is presented. A ThermoFluor (thermal shift) and a fluorescence resonance energy transfer enzymatic screen on the soluble domain of BACE1, together with a surface plasmon resonance (SPR) screen on the soluble domain of BACE1 and a mutant of one catalytic Asp (D32N), were run in parallel. Fragments that were active in at least two of these assays were further confirmed using one-dimensional NMR (WaterLOGSY) and SPR binding competition studies with peptidic inhibitor OM99-2. Protein-observed NMR (two-dimensional 15N heteronuclear single-quantum coherence spectroscopy) and crystallographic studies with the soluble domain of BACE1 identified a unique and novel binding mode for compound 12, a fragment that still occupies the active site while not making any interactions with catalytic Asps. This novel approach of combining orthogonal fragment screening techniques, for both wild-type and mutant enzymes, as well as binding competition studies could be generalized to other targets to overcome undesired interaction motifs and as a hit-generation approach in highly constrained intellectual property space.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Fragment Binding to β-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches

et al. 2017

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“…1 (supplemental materials are available at http://jnm.snmjournals.org). JNJ-49146981 is a potent brain-penetrating BACE inhibitor with a half-maximal inhibitory concentration of 4.6 nM in an enzymatic BACE1 assay and 0.9 nM in a cellular assay measuring reduction in Ab42 levels (20). Further pharmacokinetic details are provided in the supplemental materials.…”

Section: Animalsmentioning

confidence: 99%

Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease

et al. 2017

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In this study, we investigated the effects of chronic administration of an inhibitor of the b-site amyloid precursor protein-cleaving enzyme 1 (BACE1) on Alzheimer-related pathology by multitracer PET imaging in transgenic APPPS1-21 (TG) mice. Methods: Wild-type (WT) and TG mice received vehicle or BACE inhibitor (60 mg/kg) starting at 7 wk of age. Outcome measures of brain metabolism, neuroinflammation, and amyloid-b pathology were obtained through small-animal PET imaging with 18 F-FDG, 18 F-peripheral benzodiazepine receptor ( 18 F-PBR), and 18 F-florbetapir ( 18 F-AV45), respectively. Baseline scans were acquired at 6-7 wk of age and follow-up scans at 4, 7, and 12 mo. 18 F-AV45 uptake was measured at 8 and 13 mo of age. After the final scans, histologic measures of amyloid-b (4G8), microglia (ionized calcium binding adaptor molecule 1), astrocytes (glial fibrillary acidic protein), and neuronal nuclei were performed. Results: TG mice demonstrated significant age-associated increases in 18 F-AV45 uptake. An effect of treatment was observed in the cortex (P 5 0.0014), hippocampus (P 5 0.0005), and thalamus (P , 0.0001). Histology confirmed reduction of amyloid-b pathology in TG-BACE mice. Regardless of treatment, TG mice demonstrated significantly lower 18 F-FDG uptake than WT mice in the thalamus (P 5 0.0004) and hippocampus (P 5 0.0332). Neuronal nucleus staining was lower in both TG groups in the thalamus and cortex. 18 F-PBR111 detected a significant age-related increase in TG mice (P , 0.0001) but did not detect the treatment-induced reduction in activated microglia as demonstrated by histology. Conclusion: Although 18 F-FDG, 18 F-PBR111, and 18 F-AV45 all detected pathologic alterations between TG and WT mice, only 18 F-AV45 could detect an effect of BACE inhibitor treatment. However, changes in WT binding of 18 F-AV45 undermine the specificity of this effect.

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“…3 Work from our laboratories has led to a series of potent BACE 1 inhibitors. 4 Among the oxazine class of BACE 1 inhibitors, compound 1 was identified as one of the most promising and was selected for further pharmacological evaluation. Toward this purpose, multigram quantities of active pharmaceutical ingredient (API) were needed.…”

Section: Introductionmentioning

confidence: 99%

Gram-Scale Synthesis of a β-Secretase 1 (BACE 1) Inhibitor

Allison

Mani

2017

ACS Omega

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Development of a scalable synthesis of an oxazine class of β-secretase inhibitor is described. Trifluoromethylated acyloin synthesis by the reaction of a mandelic acid with trifluoroacetic anhydride in the presence of pyridine (Dakin–West reaction) was used as an efficient strategy to install the key trifluoromethyl substituent on the oxazine ring. Diastereoselective addition of methyl magnesium bromide to a cyclic sulfamidate imine and trimethylsilyl trifluoromethanesulfonate catalyzed intramolecular amidine formation to yield oxazine-3-amine are some of the significant, novel synthetic methods developed in this synthesis. These critical transformations allowed a concise 11-step route to the target compound with excellent overall yields.

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1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads

Cited by 70 publications

References 30 publications

Fragment Binding to β-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches

Fragment Binding to β-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches

Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease

Gram-Scale Synthesis of a β-Secretase 1 (BACE 1) Inhibitor

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