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

ABSTRACT: Development of a scalable synthesis of an oxazine class of ?-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.

SUBMITTER: Allison BD

PROVIDER: S-EPMC6044763 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Allison Brett D BD Mani Neelakandha S NS

ACS omega 20170203 2

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 intramol ...[more]

PMID: 30023606

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Discovery of potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids.

Project description:AimThe aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease beta-secretase (BACE-1) bearing hydroxyethylene (HE) framework.MethodsFirst, we designed the small library based on our previous work and rational analysis. Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity. We then used molecular modeling to explain the possible binding mode.ResultsThirteen new compounds (6-18) have been designed, synthesized and bioassayed. Their structures were determined by nuclear magnetic resonance (NMR) spectra, low- and high-resolution mass spectra and optical rotation. Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck. The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study.ConclusionThis study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer's disease.

| S-EPMC4002469 | biostudies-literature

Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.

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| S-EPMC1973166 | biostudies-literature

Application of consensus scoring and principal component analysis for virtual screening against β-secretase (BACE-1).

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| S-EPMC3372491 | biostudies-literature

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| S-EPMC6715607 | biostudies-literature

BACE-1 inhibition prevents the γ-secretase inhibitor evoked Aβ rise in human neuroblastoma SH-SY5Y cells.

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| S-EPMC3217850 | biostudies-literature

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| S-EPMC2862695 | biostudies-literature

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| S-EPMC8278928 | biostudies-literature

BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer's Disease.

Project description:Alzheimer's disease (AD) is a growing global health concern with a massive impact on affected individuals and society. Despite the considerable advances achieved in the understanding of AD pathogenesis, researchers have not been successful in fully identifying the mechanisms involved in disease progression. The amyloid hypothesis, currently the prevalent theory for AD, defends the deposition of β-amyloid protein (Aβ) aggregates as the trigger of a series of events leading to neuronal dysfunction and dementia. Hence, several research and development (R&D) programs have been led by the pharmaceutical industry in an effort to discover effective and safety anti-amyloid agents as disease modifying agents for AD. Among 19 drug candidates identified in the AD pipeline, nine have their mechanism of action centered in the activity of β or γ-secretase proteases, covering almost 50% of the identified agents. These drug candidates must fulfill the general rigid prerequisites for a drug aimed for central nervous system (CNS) penetration and selectivity toward different aspartyl proteases. This review presents the classes of γ-secretase and beta-site APP cleaving enzyme 1 (BACE-1) inhibitors under development, highlighting their structure-activity relationship, among other physical-chemistry aspects important for the successful development of new anti-AD pharmacological agents.

| S-EPMC6469197 | biostudies-literature

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Project description:The regioselective difunctionalization of cyclodextrins (CDs) leading to derivatives amenable to further transformations is a daunting task due to challenging purification and unambiguous characterization of the obtained regioisomers with similar physicochemical properties. The primary-side homo-difunctionalization of β-CD can lead to three regioisomers, while the hetero-difunctionalization can generate three pairs of pseudoenantiomers. Previously, approaches with several synthetic steps, expensive reagents, high purification demands and low yields of the products have been employed. Herein we present direct, short and efficient primary-side difunctionalization strategies featuring reproducibility, ease of product purification, scalability of the reactions and versatility of the substituents introduced. Specifically, the prepared ditosylated β-CDs were separated using preparative reversed-phase column chromatography and their structures were elucidated by NMR experiments. Azidation led to the corresponding pure diazido regioisomers. Direct monotosylation of 6-monoazido-β-CD or monoazidation of the single regioisomers 6A,6X-ditosyl-β-CDs afforded hetero-difunctionalized 6A-monoazido-6X-tosyl-β-CDs in significant yields. Overall, the single regioisomers, 6A,6X-ditosyl-, 6A,6X-diazido- and 6A-monoazido-6X-monotosyl-β-CD were prepared in one or two steps and purified in multigram scale thus opening the way towards further selective and orthogonal functionalizations of β-CD hosts.

| S-EPMC6444459 | biostudies-literature

Creation of Novel Cores for ?-Secretase (BACE-1) Inhibitors: A Multiparameter Lead Generation Strategy.

Project description:In order to find optimal core structures as starting points for lead optimization, a multiparameter lead generation workflow was designed with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. De novo design of core fragments was connected with three predictive in silico models addressing target affinity, permeability, and hERG activity, in order to guide synthesis. Taking advantage of an additive SAR, the prioritized cores were decorated with a few, well-characterized substituents from known BACE-1 inhibitors in order to allow for core-to-core comparisons. Prediction methods and analyses of how physicochemical properties of the core structures correlate to in vitro data are described. The syntheses and in vitro data of the test compounds are reported in a separate paper by Ginman et al. [J. Med. Chem. 2013, 56, 4181-4205]. The affinity predictions are described in detail by Roos et al. [J. Chem. Inf. 2014, DOI: 10.1021/ci400374z].

| S-EPMC4027760 | biostudies-literature

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