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Chemical Formula: C26H42N2O6
Molecular Weight: 478.63
Elemental Analysis: C, 65.25; H, 8.85; N, 5.85; O, 20.06
ZGN-1061; ZGN1061; ZGN 1061; Aclimostat,
(3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3- methylbut-2-en-1-yl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl 3-[2-(morpholin-4-yl)ethyl]azetidine-1-carboxylate
1-Azetidinecarboxylic acid, 3-[2-(4-morpholinyl)ethyl]-, (3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-buten-1-yl)-2-oxiranyl]-1-oxaspiro[2.5]oct-6-yl ester
3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 3-(2-morpholinoethyl)azetidine-1-carboxylate
ZAFGEN, PHASE 2, DIABETES
Aclimostat, also known as ZGN-1061, is an anti-diabetic, anti-obesity MetAP2 inhibitor.
Over 1.1 billion people worldwide are reported to be overweight. Obesity is estimated to affect over 90 million people in the United States alone. Twenty-five percent of the population in the United States over the age of twenty is considered clinically obese. While being overweight or obese presents problems (for example restriction of mobility, discomfort in tight spaces such as theater or airplane seats, social difficulties, etc.), these conditions, in particular clinical obesity, affect other aspects of health, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being overweight or obese. The estimated mortality from obesity-related conditions in the United States is over 300,000 annually (O’Brien et al. Amer J Surgery (2002) 184:4S-8S; and Hill et al. (1998) Science, 280:1371).  There is no curative treatment for being overweight or obese. Traditional pharmacotherapies for treating an overweight or obese subject, such as serotonin and noradrenergic re-uptake inhibitors, noradrenergic re-uptake inhibitors, selective serotonin re- uptake inhibitors, intestinal lipase inhibitors, or surgeries such as stomach stapling or gastric banding, have been shown to provide minimal short-term benefits or significant rates of relapse, and have further shown harmful side-effects to patients.  MetAP2 encodes a protein that functions at least in part by enzymatically removing the amino terminal methionine residue from certain newly translated proteins such as glyceraldehyde-3-phosphate dehydrogenase (Warder et al. (2008) J. Proteome Res.7:4807). Increased expression of the MetAP2 gene has been historically associated with various forms of cancer. Molecules inhibiting the enzymatic activity of MetAP2 have been identified and have been explored for their utility in the treatment of various tumor types (Wang et al. (2003) Cancer Res.63:7861) and infectious diseases such as microsporidiosis, leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci.9:34). Notably, inhibition of MetAP2 activity in obese and obese-diabetic animals leads to a reduction in body weight in part by increasing the oxidation of fat and in part by reducing the consumption of food (Rupnick et al. (2002) Proc. Natl. Acad. Sci. USA 99:10730).
 Such MetAP2 inhibitors may be useful as well for patients with excess adiposity and conditions related to adiposity including type 2 diabetes, hepatic steatosis, and
cardiovascular disease (via e.g. ameliorating insulin resistance, reducing hepatic lipid content, and reducing cardiac workload). Accordingly, compounds capable of modulating MetAP2 are needed to address the treatment of obesity and related diseases as well as other ailments favorably responsive to MetAP2 modulator treatment.
Tetrahedron, 73(30), 4371-4379; 2017
(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 3-(2-morpholinoethyl)azetidine-1-carboxylate
 To a mixture of 4-(2-(azetidin-3-yl)ethyl)morpholine, trifluoroacetate (2.33 g, 3.7 mmol) in CH3CN (150 mL) was added DIPEA (2.9 mL, 17 mmol) drop-wise at 0-5oC. The mixture was then stirred at 0-5oC for 10 min, and carbonate Intermediate 1 (1.3 g, 2.9 mmol) was added to the mixture in portions at 0oC under a N2atmosphere. The reaction mixture was stirred at 25oC for 16 hrs. TLC (PE : EtOAc = 3 : 1) showed that the reaction was complete. The solvent was removed under vacuum below 40oC. The residue was diluted with DCM (60 mL), and the DCM solution was washed with ammonium acetate buffer (pH~4, 15 mL x 2). The combined aqueous layers were back-extracted with DCM (20 mL x 2). The combined organic layers were washed with aq. NaHCO3 solution (15 mL x 2, 5% wt), dried over Na2SO4 and concentrated. Purification by silica gel column chromatography (DCM: MeOH=100: 0~60: 1), followed by preparative HPLC (Method A, H2O (0.1% FA) / CH3CN) gave the title compound (1.15 g) as a light yellow syrup. LC-MS: m/z = 479 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 5.43 (br, 1H), 5.13 (t, J = 7.6 Hz, 1H), 3.87-4.15 (m, 2H), 3.63-3.65 (m, 4H), 3.52- 3.56 (m, 3H), 3.49 (s, 3H), 2.90 (d, J = 4.4 Hz, 1H), 2.46-2.54 (m, 3H), 2.19-2.36 (m, 7H), 1.97-2.13 (m, 2H), 1.78-1.89 (m, 5H), 1.73 (s, 3H), 1.62 (s, 3H), 1.13 (s, 3H), 0.99 (d, J = 13.6 Hz, 1H).
1: Malloy J, Zhuang D, Kim T, Inskeep P, Kim D, Taylor K. Single and multiple dose evaluation of a novel MetAP2 inhibitor: Results of a randomized, double-blind, placebo-controlled clinical trial. Diabetes Obes Metab. 2018 Aug;20(8):1878-1884. doi: 10.1111/dom.13305. Epub 2018 Apr 23. PubMed PMID: 29577550; PubMed Central PMCID: PMC6055687.
2: Burkey BF, Hoglen NC, Inskeep P, Wyman M, Hughes TE, Vath JE. Preclinical Efficacy and Safety of the Novel Antidiabetic, Antiobesity MetAP2 Inhibitor ZGN-1061. J Pharmacol Exp Ther. 2018 May;365(2):301-313. doi: 10.1124/jpet.117.246272. Epub 2018 Feb 28. PubMed PMID: 29491038.
//////////////Aclimostat, ZGN-1061, ZAFGEN, PHASE 2, DIABETES
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.
- 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.
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. 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. 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. 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.
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
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
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
* To whom correspondence should be addressed. Phone: (617)-252-6920, extension 2129. Fax: (617)-252-6924. E-mail: email@example.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)
- 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.
- 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.
|Chemical and physical data|
|Molar mass||469.560 g/mol g·mol−1|
|3D model (JSmol)|
////////////SRT-1720 DI HCl, obesity, diabetes, SRT 1720, Sirtris Pharmaceuticals, CAY10559, CAY 10559, Preclinical