1009816-48-1 Usage
Description
Thiamet G (1009816-48-1) is a potent and selective inhibitor of O-GlcNAcase, with a Ki of 21 nM for human O-GlcNAcase. It increases levels of O-GlcNAc-modified proteins in cellular assays and in vivo, suppresses phosphorylation of tau protein in rat cortex and hippocampus, stabilizes tau against aggregation, slows neurodegeneration, prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice, elevates soluble tau species, and reduces tauopathy in mouse models. Thiamet G is active in vivo and is blood-brain barrier permeable.
Uses
Used in Pharmaceutical Industry:
Thiamet G is used as an anti-Alzheimer's agent for its ability to block pathological hyperphosphorylation of tau in Alzheimer's disease. It has the potential to probe the functional role of O-GlcNAc in vertebrate brain and may offer a route to blocking pathological hyperphosphorylation of tau.
Used in Research Applications:
Thiamet G is used as a potent O-GlcNAcase inhibitor in research settings to study the role of O-GlcNAc in various cellular processes and its impact on neurodegenerative diseases, particularly Alzheimer's disease.
Biochem/physiol Actions
Thiamet G is a potent inhibitor of the enzyme O-GlcNAcase (Ki = 21 nM). The compound is orally bioavailable and crosses the blood brain barrier. Thiamet G leads to an increase in O-GlcNAc-modified proteins in cell-based and in vivo assay systems, and reduces levels of phosphorylated Tau protein in rat cortex and hippocampus.
References
1) Yuzwa?et al. (2008),?A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo; Nat. Chem. Biol.,?4?483
2) Yuzwa?et al. (2012),?Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation; Nat. Chem. Biol.?8?393
3) Yuzwa?et al. (2014),?Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice; Mol. Neurodegener.,?9?42
4) Hastings?et al.?(2017)?Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice;?Mol. Neurodegener.,?12?39
Check Digit Verification of cas no
The CAS Registry Mumber 1009816-48-1 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,0,0,9,8,1 and 6 respectively; the second part has 2 digits, 4 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 1009816-48:
(9*1)+(8*0)+(7*0)+(6*9)+(5*8)+(4*1)+(3*6)+(2*4)+(1*8)=141
141 % 10 = 1
So 1009816-48-1 is a valid CAS Registry Number.
1009816-48-1Relevant articles and documents
Analysis of transition state mimicry by tight binding aminothiazoline inhibitors provides insight into catalysis by human: O-GlcNAcase
Cekic,Heinonen,Stubbs,Roth,He,Bennet,McEachern,Davies,Vocadlo
, p. 3742 - 3750 (2016/06/09)
The modification of nucleocytoplasmic proteins with O-linked N-Acetylglucosamine (O-GlcNAc) plays diverse roles in multicellular organisms. Inhibitors of O-GlcNAc hydrolase (OGA), the enzyme that removes O-GlcNAc from proteins, lead to increased O-GlcNAc levels in cells and are seeing widespread adoption in the field as a research tool used in cells and in vivo. Here we synthesize and study a series of tight binding carbohydrate-based inhibitors of human OGA (hOGA). The most potent of these 2′-Aminothiazolines binds with a sub-nanomolar Ki value to hOGA (510 ± 50 pM) and the most selective has greater than 1800000-fold selectivity for hOGA over mechanistically related human lysosomal β-hexosaminidase. Structural data of inhibitors in complex with an hOGA homologue reveals the basis for variation in binding among these compounds. Using linear free energy analyses, we show binding of these 2′-Aminothiazoline inhibitors depends on the pKa of the aminothiazoline ring system, revealing the protonation state of the inhibitor is a key driver of binding. Using series of inhibitors and synthetic substrates, we show that 2′-Aminothiazoline inhibitors are transition state analogues of hOGA that bind to the enzyme up to 1-million fold more tightly than the substrate. These collective data support an oxazoline, rather than a protonated oxazolinium ion, intermediate being formed along the reaction pathway. Inhibitors from this series will prove generally useful tools for the study of O-GlcNAc. The new insights gained here, into the catalytic mechanism of hOGA and the fundamental drivers of potency and selectivity of OGA inhibitors, should enable tuning of hOGA inhibitors with desirable properties.
SELECTIVE GLYCOSIDASE INHIBITORS AND USES THEREOF
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Page/Page column 54; 66; 68, (2008/06/13)
The invention provides compounds of formula (I) for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds The invention also provides methods of treating diseas
