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162635-04-3

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162635-04-3 Usage

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

Uses

Different sources of media describe the Uses of 162635-04-3 differently. You can refer to the following data:
1. 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.
2. Temsirolimus (CCI-779) is a specific mTOR inhibitor with IC50 of 1.76 μM.
3. 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.
4. 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

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.

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.

Check Digit Verification of cas no

The CAS Registry Mumber 162635-04-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,6,2,6,3 and 5 respectively; the second part has 2 digits, 0 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 162635-04:
(8*1)+(7*6)+(6*2)+(5*6)+(4*3)+(3*5)+(2*0)+(1*4)=123
123 % 10 = 3
So 162635-04-3 is a valid CAS Registry Number.
InChI:InChI=1/C56H87NO16/c1-33-17-13-12-14-18-34(2)45(68-9)29-41-22-20-39(7)56(67,73-41)51(63)52(64)57-24-16-15-19-42(57)53(65)71-46(30-43(60)35(3)26-38(6)49(62)50(70-11)48(61)37(5)25-33)36(4)27-40-21-23-44(47(28-40)69-10)72-54(66)55(8,31-58)32-59/h12-14,17-18,26,33,35-37,39-42,44-47,49-50,58-59,62,67H,15-16,19-25,27-32H2,1-11H3/b14-12+,17-13+,34-18+,38-26+/t33-,35-,36-,37-,39-,40+,41+,42+,44-,45+,46+,47-,49-,50+,56-/m1/s1

162635-04-3SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 17, 2017

Revision Date: Aug 17, 2017

1.Identification

1.1 GHS Product identifier

Product name Temsirolimus

1.2 Other means of identification

Product number -
Other names CCL-779

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:162635-04-3 SDS

162635-04-3Relevant articles and documents

Temsirolimus intermediate compound

-

, (2022/03/17)

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a temsirolimus intermediate compound. The preparation method of the temsirolimus intermediate compound comprises the following steps: inert gas protection, addition of a compound VI and a compound VII into an organic solvent A, addition of organic alkali, temperature control reaction, TLC detection, addition of a solvent B for dilution after the reaction is finished, drying with anhydrous sodium sulfate, and vacuum concentration, thereby obtaining a compound I. The invention provides the novel temsirolimus intermediate compound I. When the compound is used for preparing temsirolimus, generation of by-products can be effectively avoided, and the synthesized intermediate does not generate new impurities; and the reaction is faster, economic and environment-friendly, yield is higher, and the method is suitable for industrial production.

Method for separating and purifying temsirolimus

-

, (2019/07/04)

The invention discloses a method for separating and purifying temsirolimus. The method comprises the following steps: (1) synthesis of a crude product; and (2) separation and purification. The specific separation and purification method has the advantages of great improvement of the purity and the yield of temsirolimus, reduction of the cost, and broad market application prospect.

Intermediate of temsirolimus and preparation method thereof

-

, (2019/01/06)

The invention provides an intermediate of temsirolimus. The intermediate has better selectivity and higher yield when used for preparation of the temsirolimus. The intermediate provided by the invention has a structural formula which is described in the specification.

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