Tideglusib

Tideglusib
Identifiers
	IUPAC name 4-Benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione;
CAS Number	865854-05-3;
PubChem CID	11313622;
ChemSpider	9488589;
UNII	Q747Y6TT42;
ChEBI	CHEBI:147398;
CompTox Dashboard (EPA)	DTXSID90235682 ;
Chemical and physical data
Formula	C19H14N2O2S
Molar mass	334.39 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C3SN(c1cccc2c1cccc2)C(=O)N3Cc4ccccc4;
	InChI InChI=1S/C19H14N2O2S/c22-18-20(13-14-7-2-1-3-8-14)19(23)24-21(18)17-12-6-10-15-9-4-5-11-16(15)17/h1-12H,13H2;

Tideglusib (NP-12, NP031112) is a potent and irreversible^[1] small molecule glycogen synthase kinase 3 (GSK-3) inhibitor.^[2]

Clinical trials

Tideglusib has been evaluated in clinical trials for:

Alzheimer's disease and progressive supranuclear palsy. Both clinical trials were discontinued in 2011 (PSP) and 2012 (Alzheimer's disease) due to lack of efficacy^[3] ^[4]^[5]^[6]^[1]
Congenital/juvenile-onset myotonic muscular dystrophy type I.^[7]

Research

Tideglusib is or has been under investigation for multiple applications:

Tooth repair mechanisms that promotes dentine reinforcement of a sponge structure until the sponge biodegrades, leaving a solid dentine structure. In 2016, the results of animal studies were reported in which 0.14 mm holes in mouse teeth were permanently filled.^[8]^[9]
Preclinical in vitro studies were carried out for neuroblastoma and ovarian cancer with significant ROS-induced apoptosis.^[10]^[11]

References

^ ^a ^b Domínguez JM, Fuertes A, Orozco L, del Monte-Millán M, Delgado E, Medina M (January 2012). "Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib". The Journal of Biological Chemistry. 287 (2): 893–904. doi:10.1074/jbc.M111.306472. PMC 3256883. PMID 22102280.
^ Mathuram TL, Reece LM, Cherian KM (August 2018). "GSK-3 Inhibitors: A Double-Edged Sword? - An Update on Tideglusib". Drug Research. 68 (8): 436–443. doi:10.1055/s-0044-100186. PMID 29388174.
^ Del Ser T (2010). "Phase IIa clinical trial on Alzheimer's disease with NP12, a GSK3 inhibitor". Alzheimer's & Dementia. 6 (4): S147. doi:10.1016/j.jalz.2010.05.455. S2CID 54293332.
^ Eldar-Finkelman H, Martinez A (2011). "GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS". Frontiers in Molecular Neuroscience. 4: 32. doi:10.3389/fnmol.2011.00032. PMC 3204427. PMID 22065134.
^ del Ser T, Steinwachs KC, Gertz HJ, Andrés MV, Gómez-Carrillo B, Medina M, et al. (2013). "Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study". Journal of Alzheimer's Disease. 33 (1): 205–215. doi:10.3233/JAD-2012-120805. PMID 22936007. S2CID 21892732.
^ "FDA Grants Fast Track Status to Tideglusib (ZentylorTM) for Progressive Supranuclear Palsy". PR Newswire Europe Including UK Disclose. 10 September 2010. ProQuest 750175748.
^ "AMO-2". AMO Pharmaceuticals. Retrieved 2017-09-21.
^ Neves VC, Babb R, Chandrasekaran D, Sharpe PT (January 2017). "Promotion of natural tooth repair by small molecule GSK3 antagonists". Scientific Reports. 7: 39654. Bibcode:2017NatSR...739654N. doi:10.1038/srep39654. PMC 5220443. PMID 28067250.
^ Gallagher J (2017-01-09). "'Tooth repair drug' may replace fillings". BBC News. Retrieved 2017-01-09.
^ Mathuram TL, Ravikumar V, Reece LM, Sasikumar CS, Cherian KM (2017). "Correlative Studies Unravelling the Possible Mechanism of Cell Death in Tideglusib-Treated Human Ovarian Teratocarcinoma-Derived PA-1 Cells". Journal of Environmental Pathology, Toxicology and Oncology. 36 (4): 321–344. doi:10.1615/JEnvironPatholToxicolOncol.2017025018. PMID 29431064.
^ Mathuram TL, Ravikumar V, Reece LM, Karthik S, Sasikumar CS, Cherian KM (September 2016). "Tideglusib induces apoptosis in human neuroblastoma IMR32 cells, provoking sub-G0/G1 accumulation and ROS generation". Environmental Toxicology and Pharmacology. 46: 194–205. doi:10.1016/j.etap.2016.07.013. PMID 27490211.

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[auto-1] Domínguez JM, Fuertes A, Orozco L, del Monte-Millán M, Delgado E, Medina M (January 2012). "Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib". The Journal of Biological Chemistry. 287 (2): 893–904. doi:10.1074/jbc.M111.306472. PMC 3256883. PMID 22102280.

[pmid29388174-2] Mathuram TL, Reece LM, Cherian KM (August 2018). "GSK-3 Inhibitors: A Double-Edged Sword? - An Update on Tideglusib". Drug Research. 68 (8): 436–443. doi:10.1055/s-0044-100186. PMID 29388174.

[3] Del Ser T (2010). "Phase IIa clinical trial on Alzheimer's disease with NP12, a GSK3 inhibitor". Alzheimer's & Dementia. 6 (4): S147. doi:10.1016/j.jalz.2010.05.455. S2CID 54293332.

[4] Eldar-Finkelman H, Martinez A (2011). "GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS". Frontiers in Molecular Neuroscience. 4: 32. doi:10.3389/fnmol.2011.00032. PMC 3204427. PMID 22065134.

[trial-5] Ser T, Steinwachs KC, Gertz HJ, Andrés MV, Gómez-Carrillo B, Medina M, et al. (2013). "Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study". Journal of Alzheimer's Disease. 33 (1): 205–215. doi:10.3233/JAD-2012-120805. PMID 22936007. S2CID 21892732.

[6] "FDA Grants Fast Track Status to Tideglusib (ZentylorTM) for Progressive Supranuclear Palsy". PR Newswire Europe Including UK Disclose. 10 September 2010. ProQuest 750175748.

[7] "AMO-2". AMO Pharmaceuticals. Retrieved 2017-09-21.

[8] Neves VC, Babb R, Chandrasekaran D, Sharpe PT (January 2017). "Promotion of natural tooth repair by small molecule GSK3 antagonists". Scientific Reports. 7: 39654. Bibcode:2017NatSR...739654N. doi:10.1038/srep39654. PMC 5220443. PMID 28067250.

[9] Gallagher J (2017-01-09). "'Tooth repair drug' may replace fillings". BBC News. Retrieved 2017-01-09.

[10] Mathuram TL, Ravikumar V, Reece LM, Sasikumar CS, Cherian KM (2017). "Correlative Studies Unravelling the Possible Mechanism of Cell Death in Tideglusib-Treated Human Ovarian Teratocarcinoma-Derived PA-1 Cells". Journal of Environmental Pathology, Toxicology and Oncology. 36 (4): 321–344. doi:10.1615/JEnvironPatholToxicolOncol.2017025018. PMID 29431064.

[11] Mathuram TL, Ravikumar V, Reece LM, Karthik S, Sasikumar CS, Cherian KM (September 2016). "Tideglusib induces apoptosis in human neuroblastoma IMR32 cells, provoking sub-G0/G1 accumulation and ROS generation". Environmental Toxicology and Pharmacology. 46: 194–205. doi:10.1016/j.etap.2016.07.013. PMID 27490211.

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