Exploring substituent diversity on pyrrolidine-aryltriazole iminosugars: Structural basis of β-glucocerebrosidase inhibition

Martı́nez-Bailén, Macarena; Carmona, Ana T.; Patterson-Orazem, Athéna C.; Lieberman, Raquel L.; Ide, Daisuke; Kubo, Moemi; Kato, Atsushi; Robina, Inmaculada; Vargas, Ângelo

doi:10.1016/j.bioorg.2019.02.025

Cited by 17 publications

(12 citation statements)

References 52 publications

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“…26 The same detrimental influence of hydroxymethyl on β-GCase inhibitory was noticed earlier by others. 30 Moreover, the D-like derivative 2 was two orders of magnitude more potent β-GCase inhibitor than its enantiomer ent-2 than only displayed an IC50 of 59.6 µM.…”

Section: Evaluation Of 2 and Ent-2 As β-Gcase Inhibitors And Kinetic mentioning

confidence: 96%

Concise asymmetric synthesis of new enantiomericC-alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease

et al. 2020

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Section: Evaluation Of 2 and Ent-2 As β-Gcase Inhibitors And Kinetic mentioning

confidence: 96%

Concise asymmetric synthesis of new enantiomericC-alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease

et al. 2020

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“…Not only the insertion of alkyl chains on the pyrrolidine core can improve the biological properties towards the GCase enzyme. The introduction of (hetero)aromatic moieties exploiting copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) can also afford more potent and selective GCase inhibitors [43], probably due to the establishment of additional interactions with the enzyme, allowing at the same time improved cell permeability and cell trafficking. In this context, Martínez-Bailén et al [44] reported the synthesis of a set of epimeric dihydroxypyrrolidines containing an aromatic moiety attached to the triazole generated in the CuAAC reaction.…”

Section: Five-membered Iminosugarsmentioning

confidence: 99%

“…The introduction of (hetero)aromatic moieties exploiting copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) can also afford more potent and selective GCase inhibitors [ 42 ], probably due to the establishment of additional interactions with the enzyme, allowing at the same time improved cell permeability and cell trafficking. In this context, Martínez-Bailén et al [ 43 ] reported the synthesis of a set of epimeric dihydroxypyrrolidines containing an aromatic moiety attached to the triazole generated in the CuAAC reaction. This new family of inhibitors exhibited a tunable biological activity towards GCase in the function of the substitution pattern of the aromatic ring, the 3,5-disubstituted derivatives being the most potent inhibitors (compounds 37 – 56 , Figure 11 ).…”

Section: Inhibitory Chaperonesmentioning

confidence: 99%

GCase Enhancers: A Potential Therapeutic Option for Gaucher Disease and Other Neurological Disorders

et al. 2022

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Pharmaceutical chaperones (PCs) are small compounds able to bind and stabilize misfolded proteins, allowing them to recover their native folding and thus their biological activity. In particular, lysosomal storage disorders (LSDs), a class of metabolic disorders due to genetic mutations that result in misfolded lysosomal enzymes, can strongly benefit from the use of PCs able to facilitate their translocation to the lysosomes. This results in a recovery of their catalytic activity. No PC for the GCase enzyme (lysosomal acid-β-glucosidase, or glucocerebrosidase) has reached the market yet, despite the importance of this enzyme not only for Gaucher disease, the most common LSD, but also for neurological disorders, such as Parkinson’s disease. This review aims to describe the efforts made by the scientific community in the last 7 years (since 2015) in order to identify new PCs for the GCase enzyme, which have been mainly identified among glycomimetic-based compounds.

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“…From the inhibition profiles of 21-24, compound 22 was found as a potent β-glucosidase inhibitor (IC 50 = 2.1 μM) and its 1R,2S,3R configuration is the same as that of pyrrolidine derivatives reported by Moreno-Vargas. [30] Taken together, it is the first study to comprehensively prepare pyrrolidine-based scaffolds and libraries for inhibition study against α-l-Rha-ase.…”

Section: Biological Evaluationmentioning

confidence: 99%

Synthesis of Nitrone‐derived Pyrrolidine Scaffolds and Their Combinatorial Libraries to Develop Selective α‐l‐Rhamnosidase Inhibitors

Chen

Sayyad

et al. 2022

Chemistry An Asian Journal

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A general and flexible approach toward the development of α‐l‐rhamnosidase (α‐l‐Rha‐ase) inhibitors is described. Five enantiopure poly‐substituted pyrrolidine‐based scaffolds bearing the C1‐aminomethyl moiety were designed and synthesized from five‐membered cyclic nitrones. Each structurally diversified amide library of these scaffolds was rapidly generated via combinatorial parallel synthesis and applied for in‐situ inhibition study against α‐l‐Rha‐ase, allowing us to efficiently identify new inhibition hits. Surprisingly, all promising inhibitors are derived from the same scaffold 3. Among them, the most potent and selective inhibitor is pyrrolidine 19 with Ki=0.24 μM, approximately 24‐fold more potent than the reference compound DAA (Ki=5.7 μM). It is the first study to comprehensively prepare pyrrolidine‐based scaffolds and libraries for inhibition study against α‐l‐Rha‐ase.

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Exploring substituent diversity on pyrrolidine-aryltriazole iminosugars: Structural basis of β-glucocerebrosidase inhibition

Cited by 17 publications

References 52 publications

Concise asymmetric synthesis of new enantiomericC-alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease

Concise asymmetric synthesis of new enantiomericC-alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease

GCase Enhancers: A Potential Therapeutic Option for Gaucher Disease and Other Neurological Disorders

Synthesis of Nitrone‐derived Pyrrolidine Scaffolds and Their Combinatorial Libraries to Develop Selective α‐l‐Rhamnosidase Inhibitors

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