Temsirolimus Property

Melting point:

99-101°C

Boiling point:

1048.4±75.0 °C(Predicted)

Density 

1.21

Flash point:

587.8℃

storage temp. 

room temp

solubility 

Soluble in chloroform, methanol.

pka

10.40±0.70(Predicted)

form 

powder

color 

white to off-white

Merck 

14,9142

InChIKey

CBPNZQVSJQDFBE-FUXHJELOSA-N

Safety

Safety Statements 

24/25

WGK Germany 

3

RTECS 

VE6257000

HS Code 

29349990

Hazardous Substances Data

162635-04-3(Hazardous Substances Data)

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Danger

Hazard statements

H360May damage fertility or the unborn child

H413May cause long lasting harmful effects to aquatic life

Precautionary statements

P201Obtain special instructions before use.

P202Do not handle until all safety precautions have been read and understood.

P273Avoid release to the environment.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P308+P313IF exposed or concerned: Get medical advice/attention.

P405Store locked up.

Temsirolimus Chemical Properties,Usage,Production

Description

While renal cell carcinoma (RCC) accounts for only 2 3% of all cancers, the 5-year survival rate for advanced RCC disease is only 5 10%, with approximately 13,000 deaths occurring annually (US statistics only). Immunotherapeutic cytokine options, such as IFN-αand IL-2, have traditionally been frontline treatments, but these agents are not efficacious in all patients and can cause serious side effects. In addition, bevacizumab, a monoclonal antibody against VEGF, has also demonstrated prolongation of PFS. The newest entry for this indication focuses on targets that are downstream from VEGF. Temsirolimus is an inhibitor of the serine/threonine kinase mTOR, which is the mammalian target of rapamycin. mTOR has been implicated in cell replication through control of the cell cycle translation of specific mRNAs. Inhibition of mTOR prevents phosphorylation of the 4E binding protein-1 and the 40S ribosomal protein S6 kinase that are responsible for cell cycle protein translation initiation; cell cycle arrest occurs as the result of termination of cell division from the G1 to the S phase. Disruption of mTOR signaling also has antiangiogenic effects that could be deemed essential in combating RCC, which is driven by unregulated angiogenesis. Temsirolimus is the 2,2-bis(hydroxymethyl)propionate ester of rapamycin (sirolimus), a macrolide fungicide isolated from the bacteria Streptomyces hygroscopicus. Similar to its parent sirolimus, temsirolimus interacts with mTOR through its complex with FK-506 binding protein 12.

Chemical Properties

White Solid

Originator

Wyeth (US)

Uses

Temsirolimus, a cell cycle inhibitor developed by Wyeth for the treatment of renal cell carcinoma, was launched in the US in 2007. Temsirolimus works by inhibiting mTOR (mammalian target of rapamycin)-driven cell proliferation. Temsirolimus is also being developed for the treatment of mantle cell lymphoma (PhIII) and also as mono- or combination therapy for the treatment of ovarian and endometrium cancer (PhII). Additionally, temsirolimus is being evaluated for the treatment of several other types of cancer as well as multiple sclerosis and rheumatoid arthritis.

Uses

Temsirolimus (CCI-779) is a specific mTOR inhibitor with IC50 of 1.76 μM.

Uses

Temsirolimus is a semisynthetic macrocyclic lactone prepared from rapamycin by selective alkylation of the 42-hydroxy group with a protected bis(dihydromethyl)propionic acid, followed by deprotection. Like all tacrolimus analogues, temsirolimus binds to receptor protein, FKBP12. The complex then binds to mTOR preventing it from interacting with target proteins. Temsirolimus is extensively cited in the literature with over 700 citations.

Uses

Temsirolimus is a semisynthetic macrocyclic lactone prepared from rapamycin by selective acylation of the 42-hydroxy group with a protected bis(dihydromethyl)propionic acid, followed by deprotection. Like all tacrolimus analogues, temsirolimus binds to receptor protein, FKBP12. The complex then binds to mTOR preventing it from interacting with target proteins. Temsirolimus is extensively cited in the literature with over 700 citations.

brand name

Torisel

General Description

Temsirolimus is an esterified derivative of rapamycinand in a similar manner binds initially to the proteinFKBP-12(FK506-binding protein).This complexthen acts to inhibit the mammalian target of rapamycin(mTOR), a serine-threonine kinase that plays a crucial rolein cell division. It is somewhat unique in its method of kinaseinhibition, because it actually binds to an allostericmodulator of the kinase rather than just binding to theATP-binding site like most other kinase inhibitors.Temsirolimus is available as a 25-mg/mL injection forIV administration in the treatment of advanced RCC. Theagent is extensively metabolized and undergoes rapid hydrolysisof the ester function to give rapamycin that retainsactivity.Additional metabolism is mediated primarilyby CYP3A4 to give several hydroxylated and demethylatedmetabolites that are inactive. The agent and metabolites areeliminated primarily in the feces with half-lives of 17 and55 hours for temsirolimus and rapamycin, respectively.This agent, like rapamycin, possesses immunosuppressantproperties and there is an increased risk of infection.The most serious side effects are interstitial lung disease,perforation of the bowel, and acute renal failure althoughthese occur only rarely. The most commonly seen side effects are rash, weakness, mucositis, nausea, edema, andanorexia.

Biochem/physiol Actions

Temsirolimus is a specific inhibitor of mammalian target of rapamycin (mTOR) mTOR Complex 1 (mTORC1). Temsirolimus is an antiproliferative and antiangiogenic, the first-in-class mTOR inhibitor approved for the treatment of patients with advanced poor prognosis renal cell carcinoma.

Clinical Use

Protein kinase inhibitor:
Treatment of advanced renal cell carcinoma
Treatment of mantle cell lymphoma

Synthesis

While rufinamide may be prepared by several related routes, the preferred starting material is 2,6-difluorobenzyl azide. Reaction with either 2-propynoic acid or 2-chloroacrylonitrile affords 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid or 1-(2,6-difluorobenzyl)- 1H-1,2,3-triazole-4-carbonitrile, respectively. For the carboxylic acid Shridhar Hegde and Michelle Schmidt intermediate, treatment with thionyl chloride followed by concentrated aqueous ammonium hydroxide or conversion to its methyl ester (methanol/sulfuric acid) with subsequent ammonolyis provides rufinamide.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: concentration increased by clarithromycin and telithromycin - avoid; concentration of both drugs increased with erythromycin; concentration of active metabolite reduced by rifampicin and rifabutin - avoid.
Antifungals: concentration increased of active metabolite increased by ketoconazole - avoid; concentration increased by fluconazole, itraconazole, miconazole, micafungin, posaconazole and voriconazole - avoid with itraconazole.
Antipsychotics: increased risk of agranulocytosis with clozapine - avoid concomitant use.
Antivirals: concentration possibly increased by atazanavir, boceprevir and lopinavir; concentration of both drugs increased with telaprevir.
Calcium-channel blockers: concentration increased by diltiazem; concentration of both drugs increased with verapamil.
Ciclosporin: increased absorption of temsirolimus - give temsirolimus 4 hours after ciclosporin; temsirolimus concentration increased; long term concomitant administration may be associated with deterioration in renal function.
Cytotoxics: use crizotinib with caution.
Grapefruit juice: concentration of temsirolimus increased - avoid.
Mycophenolate: concomitant use of mycophenolate and sirolimus increases plasma levels of both temsirolimus and mycophenolic acid.

Metabolism

Mainly metabolised by cytochrome P450 isoenzyme CYP3A4 to 5 metabolites; sirolimus is the main active metabolite, there is increased exposure to sirolimus compared with temsirolimus due to longer half-life of sirolimus.
Elimination is mainly in faeces; about 5% is recovered in the urine.

storage

Store at -20°C

References

[1] yu k, toral-barza l, discafani c, et al. mtor, a novel target in breast cancer: the effect of cci-779, an mtor inhibitor, in preclinical models of breast cancer. endocrine-related cancer, 2001, 8(3): 249-258.
[2] frost p, moatamed f, hoang b, et al. in vivo antitumor effects of the mtor inhibitor cci-779 against human multiple myeloma cells in a xenograft model. blood, 2004, 104(13): 4181-4187.