SRT-1720

SRT-1720
Identifiers
	IUPAC name N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b] [1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide;
CAS Number	925434-55-5 ;
PubChem CID	24180125;
IUPHAR/BPS	7703;
ChemSpider	20581461;
UNII	DX3FHY76FZ;
CompTox Dashboard (EPA)	DTXSID00636045 ;
Chemical and physical data
Formula	C25H23N7OS
Molar mass	469.57 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C6CNCCN6Cc(n1c5)csc1nc5-c3ccccc3NC(=O)c4cnc2ccccc2n4;
	InChI InChI=1S/C25H23N7OS/c33-24(22-13-27-20-7-3-4-8-21(20)28-22)29-19-6-2-1-5-18(19)23-15-32-17(16-34-25(32)30-23)14-31-11-9-26-10-12-31/h1-8,13,15-16,26H,9-12,14H2,(H,29,33); Key:IASPBORHOMBZMY-UHFFFAOYSA-N;
	(verify)

SRT-1720 is an experimental drug that was studied by Sirtris Pharmaceuticals intended as a small-molecule activator of the sirtuin subtype SIRT1. The compound has been studied in animals, but safety and efficacy in humans have not been established.

Animal research

In animal models of obesity and diabetes SRT1720 was found to improve insulin sensitivity and lower plasma glucose levels in fat, muscle and liver tissue, and increase mitochondrial and metabolic function.^[1] In mice rendered obese and diabetic by feeding a high-fat, high-sugar diet, a study performed at the National Institute of Aging found that feeding chow infused with the highest dose of SRT1720 beginning at one year of age increased mean lifespan by 18%, and maximum lifespan by 5%, as compared to other short-lived obese, diabetic mice; however, treated animals still lived substantially shorter lives than normal-weight mice fed normal chow with no drug.^[2] In a later study, SRT1720 increased mean lifespan of obese, diabetic mice by 21.7%, similar to the earlier study, but there was no effect on maximum lifespan in this study.^[3] In normal-weight mice fed a standard rodent diet, SRT1720 increased mean lifespan by just 8.8%, and again had no effect on maximum lifespan.^[3]

Since the discovery of SRT1720, the claim that this compound is a SIRT1 activator has been questioned^[4]^[5]^[6] and further defended.^[7]^[8]

Although SRT1720 is not currently undergoing clinical development, a related compound, SRT2104, reached Phase II human trials for metabolic diseases.^[9]

References

^ Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, et al. (November 2007). "Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes". Nature. 450 (7170): 712–6. Bibcode:2007Natur.450..712M. doi:10.1038/nature06261. PMC 2753457. PMID 18046409.
^ Minor RK, Baur JA, Gomes AP, Ward TM, Csiszar A, Mercken EM, et al. (Aug 2011). "SRT1720 improves survival and healthspan of obese mice". Scientific Reports. 1 (70): 70. Bibcode:2011NatSR...1E..70M. doi:10.1038/srep00070. PMC 3216557. PMID 22355589.
^ ^a ^b Mitchell SJ, Martin-Montalvo A, Mercken EM, Palacios HH, Ward TM, Abulwerdi G, et al. (March 2014). "The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet". Cell Reports. 6 (5): 836–43. doi:10.1016/j.celrep.2014.01.031. PMC 4010117. PMID 24582957.
^ Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, et al. (March 2010). "SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1". The Journal of Biological Chemistry. 285 (11): 8340–51. doi:10.1074/jbc.M109.088682. PMC 2832984. PMID 20061378.
^ Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M (December 2009). "Resveratrol is not a direct activator of SIRT1 enzyme activity". Chemical Biology & Drug Design. 74 (6): 619–24. doi:10.1111/j.1747-0285.2009.00901.x. PMID 19843076. S2CID 205913187.
^ Zarse K, Schmeisser S, Birringer M, Falk E, Schmoll D, Ristow M (November 2010). "Differential effects of resveratrol and SRT1720 on lifespan of adult Caenorhabditis elegans". Hormone and Metabolic Research. 42 (12): 837–9. doi:10.1055/s-0030-1265225. PMID 20925017. S2CID 260168892.
^ Callaway E (2010-08-16). "GlaxoSmithKline strikes back over anti-ageing pills: Drugs do work as thought, says pharmaceutical giant". Nature. doi:10.1038/news.2010.412.
^ Dai H, Kustigian L, Carney D, Case A, Considine T, Hubbard BP, et al. (October 2010). "SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator". The Journal of Biological Chemistry. 285 (43): 32695–703. doi:10.1074/jbc.M110.133892. PMC 2963390. PMID 20702418.
^ "Sirtuin Pipeline". Sirtris Pharmaceuticals.
^ Thevis M, Schänzer W (March 2016). "Emerging drugs affecting skeletal muscle function and mitochondrial biogenesis - Potential implications for sports drug testing programs". Rapid Communications in Mass Spectrometry. 30 (5): 635–51. Bibcode:2016RCMS...30..635T. doi:10.1002/rcm.7470. PMID 26842585. S2CID 206444739.

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[pmid18046409-1] Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, et al. (November 2007). "Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes". Nature. 450 (7170): 712–6. Bibcode:2007Natur.450..712M. doi:10.1038/nature06261. PMC 2753457. PMID 18046409.

[Minor2011-2] Minor RK, Baur JA, Gomes AP, Ward TM, Csiszar A, Mercken EM, et al. (Aug 2011). "SRT1720 improves survival and healthspan of obese mice". Scientific Reports. 1 (70): 70. Bibcode:2011NatSR...1E..70M. doi:10.1038/srep00070. PMC 3216557. PMID 22355589.

[Mitchell2014-3] Mitchell SJ, Martin-Montalvo A, Mercken EM, Palacios HH, Ward TM, Abulwerdi G, et al. (March 2014). "The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet". Cell Reports. 6 (5): 836–43. doi:10.1016/j.celrep.2014.01.031. PMC 4010117. PMID 24582957.

[pmid20061378-4] Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, et al. (March 2010). "SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1". The Journal of Biological Chemistry. 285 (11): 8340–51. doi:10.1074/jbc.M109.088682. PMC 2832984. PMID 20061378.

[pmid19843076-5] Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M (December 2009). "Resveratrol is not a direct activator of SIRT1 enzyme activity". Chemical Biology & Drug Design. 74 (6): 619–24. doi:10.1111/j.1747-0285.2009.00901.x. PMID 19843076. S2CID 205913187.

[6] Zarse K, Schmeisser S, Birringer M, Falk E, Schmoll D, Ristow M (November 2010). "Differential effects of resveratrol and SRT1720 on lifespan of adult Caenorhabditis elegans". Hormone and Metabolic Research. 42 (12): 837–9. doi:10.1055/s-0030-1265225. PMID 20925017. S2CID 260168892.

[7] Callaway E (2010-08-16). "GlaxoSmithKline strikes back over anti-ageing pills: Drugs do work as thought, says pharmaceutical giant". Nature. doi:10.1038/news.2010.412.

[pmid20702418-8] Dai H, Kustigian L, Carney D, Case A, Considine T, Hubbard BP, et al. (October 2010). "SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator". The Journal of Biological Chemistry. 285 (43): 32695–703. doi:10.1074/jbc.M110.133892. PMC 2963390. PMID 20702418.

[9] "Sirtuin Pipeline". Sirtris Pharmaceuticals.

[pmid26842585-10] Thevis M, Schänzer W (March 2016). "Emerging drugs affecting skeletal muscle function and mitochondrial biogenesis - Potential implications for sports drug testing programs". Rapid Communications in Mass Spectrometry. 30 (5): 635–51. Bibcode:2016RCMS...30..635T. doi:10.1002/rcm.7470. PMID 26842585. S2CID 206444739.

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Animal research

See also

References