SRT-1720

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SRT-1720 diHCl

CAY10559

CAS: 1001645-58-4 (di HCl) , 925434-55-5 (free base) 1001645-58-4 (HCl)
Chemical Formula: C25H25Cl2N7OS
Molecular Weight: 542.483
Elemental Analysis: C, 55.35; H, 4.65; Cl, 13.07; N, 18.07; O, 2.95; S, 5.91

SRT-1720 HCl, SRT-1720 hudrochloride; SRT1720; SRT-1720; SRT 1720; CAY10559; CAY-10559; CAY 10559; SIRT-1933; SIRT 1933; SIRT1933.

N-(2-(3-(piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)quinoxaline-2-carboxamide dihydrochloride

Molecular FormulaC₂₅H₂₃N₇OS
Average mass469.561 Da

SRT-1720, also known as CAY10559 and is a drug developed by Sirtris Pharmaceuticals intended as a small-molecule activator of the sirtuin subtype SIRT1. It has similar activity in the body to the known SIRT1 activator resveratrol, but is 1000x more potent. In animal studies it was found to improve insulin sensitivity and lower plasma glucose levels in fat, muscle and liver tissue, and increased mitochondrial and metabolic function. A study of SRT1720 conducted by the National Institute on Aging found that the drug may extend the lifespan of obese mice by 44% .

SRT1720 is an experimental drug that was studied by Sirtris Pharmaceuticals intended as a small-molecule activator of the sirtuinsubtype 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, is currently in clinical development for metabolic diseases.^[9]

PAPER

Letters in Drug Design & Discovery, 10(9), 793-797; 2013

The Identification of the SIRT1 Activator SRT2104 as a Clinical Candidate

Author(s): Pui Yee Ng, Jean E. Bemis, Jeremy S. Disch, Chi B. Vu, Christopher J. Oalmann, Amy V. Lynch,David P. Carney, Thomas V. Riera, Jeffrey Song, Jesse J. Smith, Siva Lavu, Angela Tornblom, Meghan Duncan, Marie Yeager, Kristina Kriksciukaite, Akanksha Gupta, Vipin Suri, Peter J. Elliot, Jill C. Milne, Joseph J. Nunes, Michael R. Jirousek, George P. Vlasuk, James L. Ellis, Robert B. Perni.

Journal Name: Letters in Drug Design & Discovery

Volume 10 , Issue 9 , 2013

DOI : 10.2174/15701808113100990021

Paper

Milne, J.C.; Lambert, P.D.; Schenk, S.; Carney, D.P.; Smith, J.J.; Gagne, D.J.; Jin, L.; Boss, O.; Perni, R.B.; Vu, C.B.; Bemis, J.E.; Xie, R.; Disch, J.S.; Ng, P.Y.; Nunes, J.J.; Lynch, A.V.; Yang, H.; Galonek, H.; Israelian, K.; Choy, W.; Iffland, A.; Lavu, S.; Medvedik, O.; Sinclair, D.A.; Olefsky, J.M.; Jirousek, M.R.; Elliott, P.J.; Westphal, C.H.
Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes
Nature 2007, 450(7170): 712

PATENT

WO 2007019417

WO 2007019416

WO 2007019345

WO 2007019344

WO 2007019346

WO 2008115518

PAPER

Vu, Chi B.; Journal of Medicinal Chemistry 2009, VOL 52(5), PG 1275-1283

https://pubs.acs.org/doi/abs/10.1021/jm8012954

A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD⁺-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.

Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators

Chi B. Vu *, Jean E. Bemis, Jeremy S. Disch, Pui Yee Ng, Joseph J. Nunes, Jill C. Milne, David P. Carney, Amy V. Lynch, Jesse J. Smith, Siva Lavu, Philip D. Lambert, David J. Gagne, Michael R. Jirousek, Simon Schenk ^†, Jerrold M. Olefsky ^† and Robert B. Perni

Sirtris Pharmaceuticals, 200 Technology Square, Cambridge, Massachusetts 02139

J. Med. Chem., 2009, 52 (5), pp 1275–1283

DOI: 10.1021/jm8012954

* To whom correspondence should be addressed. Phone: (617)-252-6920, extension 2129. Fax: (617)-252-6924. E-mail: cvu@sirtrispharma.com., †

Present address: Department of Medicine, Division of Endocrinology and Metabolism, University of California—San Diego, 9500 Gilman Drive, La Jolla, CA 92093.

Preparation of N-(2-(3-(Piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)quinoxaline-2-carboxamide (29)

Essentially the same procedure as detailed in the preparation of 3,4,5-trimethoxy-N-(2-(3-(piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)benzamide was employed except that 2-quinoxaloyl chloride was used.

Mp: dec (HCl salt), 221.4 °C (freebase).

¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (br s, 1 H), 8.88 (d, 1 H, J = 8 Hz), 8.60 (br s, 1 H), 8.50 (s, 1 H), 8.0−8.30 (m, 5 H), 7.78 (d, 1 H, J = 8 Hz), 7.10−7.33 (m, 4 H), 3.90 (br s, 2 H), 3.00−3.10 (m, 4H), 2.60−2.80 (m, 4 H).

¹³C NMR (100 MHz, DMSO-d₆): δ 47.49, 49.88, 111.45, 120.47, 121.84, 124.02, 127.04, 128.10, 129.20, 129.23, 131.39, 132.15, 135.39, 139.54, 143.03, 143.80, 144.36, 144.62, 147.76, 161.57.

High resolution MS, calcd for C₂₅H₂₃N₇OS [M + H]⁺ 470.1763; found, 470.1753.

References

^ Milne JC; Lambert PD; Schenk S; Carney DP; Smith JJ; Gagne DJ; Jin L; Boss O; Perni RB; Vu CB; Bemis JE; Xie R; Disch JS; Ng PY; Nunes JJ; Lynch AV; Yang H; Galonek H; Israelian K; Choy W; Iffland A; Lavu S; Medvedik O; Sinclair DA; Olefsky JM; Jirousek MR; Elliott PJ; Westphal CH (November 2007). “Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes”. Nature. 450(7170): 712–6. doi:10.1038/nature06261. PMC 2753457. PMID 18046409.
^ Minor RK; Baur JA; Gomes AP; Ward TM; Csiszar A; Mercken EM; Abdelmohsen K; Shin YK; Canto C; Scheibye-Knudsen M; Krawczyk M; Irusta PM; Martín-Montalvo A; Hubbard BP; Zhang Y; Lehrmann E; White AA; Price NL; Swindell WR; Pearson KJ; Becker KG; Bohr VA; Gorospe M; Egan JM; Talan MI; Auwerx J; Westphal CH; Ellis JL; Ungvari Z; Vlasuk GP; Elliott PJ; Sinclair DA; de Cabo R (Aug 2011). “SRT1720 improves survival and healthspan of obese mice”. Scientific Reports. 1 (70): 70. doi:10.1038/srep00070. PMC 3216557. PMID 22355589. Retrieved 1 March 2014.
^ Jump up to:^a ^b Mitchell SJ; Martin-Montalvo A; Mercken EM; et al. (Feb 2014). “The SIRT1 Activator SRT1720 Extends Lifespan and Improves Health of Mice Fed a Standard Diet”. Cell Reports. 6 (4): 836–43. doi:10.1016/j.celrep.2014.01.031. PMC 4010117. PMID 24582957. Retrieved 1 March 2014.
^ Pacholec M; Chrunyk BA; Cunningham D; Flynn D; Griffith DA; Griffor M; Loulakis P; Pabst B; Qiu X; Stockman B; Thanabal V; Varghese A; Ward J; Withka J; Ahn K (January 2010). “SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1”. J Biol Chem. 285 (11): 8340–8351. 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”. Chem Biol Drug Des. 74 (6): 619–24. doi:10.1111/j.1747-0285.2009.00901.x. PMID 19843076.
^ Zarse, K.; Schmeisser, S.; Birringer, M.; Falk, E.; Schmoll, D.; Ristow, M. (2010). “Differential Effects of Resveratrol and SRT1720 on Lifespan of AdultCaenorhabditis elegans”. Hormone and Metabolic Research. 42 (12): 837–839. doi:10.1055/s-0030-1265225. PMID 20925017.
^ 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; Perni RB; Riera TV; Szczepankiewicz B; Vlasuk GP; Stein RL (August 2010). “SIRT1 activation by small molecules – kinetic and biophysical evidence for direct interaction of enzyme and activator”. J Biol Chem. 285 (43): 32695–32703. doi:10.1074/jbc.M110.133892. PMC 2963390. PMID 20702418.
^ “Sirtuin Pipeline”. Sirtris Pharmaceuticals.

SRT1720
Identifiers

IUPAC name [show]
PubChem CID	24180125
IUPHAR/BPS	7703
ChemSpider	20581461
CompTox Dashboard(EPA)	DTXSID00636045
Chemical and physical data
Formula	C₂₅H₂₃N₇OS
Molar mass	469.560 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] C6CNCCN6Cc(n1c5)csc1nc5-c3ccccc3NC(=O)c4cnc2ccccc2n4
InChI [hide] 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

////////////SRT-1720 DI HCl, obesity, diabetes, SRT 1720, Sirtris Pharmaceuticals, CAY10559, CAY 10559, Preclinical

O=C(NC1=CC=CC=C1C2=CN3C(SC=C3CN4CCNCC4)=N2)C5=NC6=CC=CC=C6N=C5.[H]Cl.[H]Cl