OSI-7904L sodium

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MedKoo CAT#: 202101

CAS#: Unknown (sodium)

Description: OSI-7904L is a novel noncompetitive liposomal thymidylate synthase inhibitor. OSI-7904 is a benzoquinazoline folate analog with antineoplastic activity. As a thymidylate synthase inhibitor, OSI-7904 noncompetitively binds to thymidylate synthase, resulting in inhibition of thymine nucleotide synthesis and DNA replication. OSI-7904L is a liposome-encapsulated formulation of OSI-7904. Liposome encapsulation improves the efficacy and increases the half-life of OSI-7904. Its effect on solid tumours is currently under evaluation.

Chemical Structure

OSI-7904L sodium
CAS# Unknown (sodium)

Theoretical Analysis

MedKoo Cat#: 202101
Name: OSI-7904L sodium
CAS#: Unknown (sodium)
Chemical Formula: C27H22N4Na2O6
Exact Mass: 500.16958
Molecular Weight: 544.47
Elemental Analysis: C, 59.56; H, 4.07; N, 10.29; Na, 8.44; O, 17.63

Price and Availability

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Related CAS #: 2197232-28-1 (racemic)   139987-54-5 (free acid)    

Synonym: OSI-7904L; OSI7904L; OSI 7904L; GS7904L; GS-7904L; GS 7904L; GW1843; GW-1843; GW 1843; 1843U89; OVI237; OVI-237; OVI 237.

IUPAC/Chemical Name: sodium (S)-2-(5-(((3-methyl-1-oxo-1,2-dihydrobenzo[f]quinazolin-9-yl)methyl)amino)-1-oxoisoindolin-2-yl)pentanedioate


InChi Code: InChI=1S/C27H24N4O6.2Na/c1-14-29-21-7-4-16-3-2-15(10-20(16)24(21)25(34)30-14)12-28-18-5-6-19-17(11-18)13-31(26(19)35)22(27(36)37)8-9-23(32)33;;/h2-7,10-11,22,28H,8-9,12-13H2,1H3,(H,32,33)(H,36,37)(H,29,30,34);;/q;2*+1/p-2/t22-;;/m0../s1

SMILES Code: O=C(O[Na])[C@@H](N(CC1=C2C=CC(NCC3=CC=C4C(C5=C(N=C(C)NC5=O)C=C4)=C3)=C1)C2=O)CCC(O[Na])=O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not soluble in water.

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Preparing Stock Solutions

The following data is based on the product molecular weight 544.47 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL

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1: Ricart AD, Berlin JD, Papadopoulos KP, Syed S, Drolet DW, Quaratino-Baker C, Horan J, Chick J, Vermeulen W, Tolcher AW, Rowinsky EK, Rothenberg ML. Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors. Clin Cancer Res. 2008 Dec 1;14(23):7947-55. PubMed PMID: 19047127.

2: Clamp AR, Schöffski P, Valle JW, Wilson RH, Marreaud S, Govaerts AS, Debois M, Lacombe D, Twelves C, Chick J, Jayson GC; EORTC New Drug Development Group. A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer. Cancer Chemother Pharmacol. 2008 Apr;61(4):579-85. Epub 2007 May 23. PubMed PMID: 17520255.

3: Ciuleanu T, Diculescu M, Hoepffner NM, Trojan J, Sailer V, Zalupski M, Herrmann T, Roth A, Chick J, Brock K, Albert D, Philip PA. A randomised phase II study of OSI-7904L versus 5-fluorouracil (FU)/leucovorin (LV) as first-line treatment in patients with advanced biliary cancers. Invest New Drugs. 2007 Aug;25(4):385-90. Epub 2007 Mar 16. PubMed PMID: 17364234.

4: Wilson RH. Novel therapeutic developments other than EGFR and VEGF inhibition in colorectal cancer. Oncologist. 2006 Oct;11(9):1018-24. Review. PubMed PMID: 17030644.

5: Falk S, Anthoney A, Eatock M, Van Cutsem E, Chick J, Glen H, Valle JW, Drolet DW, Albert D, Ferry D, Ajani J. Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma. Br J Cancer. 2006 Aug 21;95(4):450-6. Epub 2006 Aug 1. PubMed PMID: 16880795; PubMed Central PMCID: PMC2360664.

6: Beutel G, Glen H, Schöffski P, Chick J, Gill S, Cassidy J, Twelves C. Phase I study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor in patients with refractory solid tumors. Clin Cancer Res. 2005 Aug 1;11(15):5487-95. PubMed PMID: 16061865.

7: Desjardins J, Emerson DL, Colagiovanni DB, Abbott E, Brown EN, Drolet DW. Pharmacokinetics, safety, and efficacy of a liposome encapsulated thymidylate synthase inhibitor, OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo- 2-isoindolynl]-glutaric acid] in mice. J Pharmacol Exp Ther. 2004 Jun;309(3):894-902. Epub 2004 Feb 24. PubMed PMID: 14982966.

1: Pang CK, Hunter JH, Gujjar R, Podutoori R, Bowman J, Mudeppa DG, Rathod PK. Catalytic and ligand-binding characteristics of Plasmodium falciparum serine hydroxymethyltransferase. Mol Biochem Parasitol. 2009 Nov;168(1):74-83. Epub 2009 Jul 8. PubMed PMID: 19591883; PubMed Central PMCID: PMC2741015.

2: Arvizu-Flores AA, Aispuro-Hernandez E, Garcia-Orozco KD, Varela-Romero A, Valenzuela-Soto E, Velazquez-Contreras EF, Rojo-Domínguez A, Yepiz-Plascencia G, Maley F, Sotelo-Mundo RR. Functional identity of the active sites of crustacean and viral thymidylate synthases. Comp Biochem Physiol C Toxicol Pharmacol. 2009 Sep;150(3):406-13. Epub 2009 Jun 25. PubMed PMID: 19559812.

3: Hunter JH, Gujjar R, Pang CK, Rathod PK. Kinetics and ligand-binding preferences of Mycobacterium tuberculosis thymidylate synthases, ThyA and ThyX. PLoS One. 2008 May 21;3(5):e2237. PubMed PMID: 18493582; PubMed Central PMCID: PMC2386288.

4: Gangjee A, Jain HD, Kurup S. Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: Part II. Anticancer Agents Med Chem. 2008 Feb;8(2):205-31. Review. PubMed PMID: 18288923.

5: Mauritz R, Peters GJ, Kathmann I, Teshale H, Noordhuis P, Comijn EM, Pinedo HM, Jansen G. Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo. Cancer Chemother Pharmacol. 2008 Nov;62(6):937-48. Epub 2008 Feb 19. PubMed PMID: 18283461.

6: Gangjee A, Jain HD, Kurup S. Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I. Anticancer Agents Med Chem. 2007 Sep;7(5):524-42. Review. PubMed PMID: 17896913.

7: Shafran A, Ifergan I, Bram E, Jansen G, Kathmann I, Peters GJ, Robey RW, Bates SE, Assaraf YG. ABCG2 harboring the Gly482 mutation confers high-level resistance to various hydrophilic antifolates. Cancer Res. 2005 Sep 15;65(18):8414-22. PubMed PMID: 16166320.

8: Temmink OH, Hoogeland MF, Fukushima M, Peters GJ. Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells. Cancer Chemother Pharmacol. 2006 Jan;57(2):171-9. Epub 2005 Jul 12. PubMed PMID: 16010590.

9: Wielinga P, Hooijberg JH, Gunnarsdottir S, Kathmann I, Reid G, Zelcer N, van der Born K, de Haas M, van der Heijden I, Kaspers G, Wijnholds J, Jansen G, Peters G, Borst P. The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates. Cancer Res. 2005 May 15;65(10):4425-30. PubMed PMID: 15899835.

10: Desjardins J, Emerson DL, Colagiovanni DB, Abbott E, Brown EN, Drolet DW. Pharmacokinetics, safety, and efficacy of a liposome encapsulated thymidylate synthase inhibitor, OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo- 2-isoindolynl]-glutaric acid] in mice. J Pharmacol Exp Ther. 2004 Jun;309(3):894-902. Epub 2004 Feb 24. PubMed PMID: 14982966.

Additional Information

Gilead licensed the compound GW1843 from GlaxoWellcome and Glaxo Group Limited (now GlaxoSmithKline) in December 2000 and reformulated the product into a liposome (now re-named GS7904L) with the goal of enhancing its antitumor activity. Both GW1843 and its liposomal formulation GS7904L have demonstrated activity in human tumor cells in vitro and antitumor activity in human tumor xenografts in mice. In the xenograft studies, the liposomal formulation showed superior efficacy. Under the terms of the agreement with GlaxoWellcome, Gilead acquired exclusive, worldwide development and commercialization rights to the compound. GS7904L is a thymidylate synthase inhibitor and belongs to the same class of agents as the anticancer drug 5-fluorouracil (5-FU). 5-FU is one of the most prescribed chemotherapeutic drugs in the world and is used for the treatment of patients with colon, breast, head and neck, stomach and pancreatic cancers. GS7904L has demonstrated potent activity in a variety of preclinical cancer models including colorectal, ileocecal and ovarian cancers. [source: http://www.allbusiness.com/medicine-health/medical-science-medical-research/6190724-1.html].
On Monday, November 26, 2001, Gilead and OSI Pharmaceuticals (Nasdaq:OSIP) announced the signing of an agreement for OSI to acquire Gilead's pipeline of clinical candidates in oncology and Gilead's Boulder, Colorado operations, including clinical research and drug development personnel and infrastructure. In consideration of these assets, OSI will pay to Gilead $130 million in cash and $40 million in shares of OSI common stock upon the closing of the transaction. OSI will also pay to Gilead up to an additional $30 million in either cash or a combination of cash and OSI common stock upon the achievement of certain milestones. The transaction is expected to close by year-end.
Interim clinical trial results: Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity. CONCLUSIONS: The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer. [source: Clin Cancer Res. 2008 Dec 1;14(23):7947-55.]