518048-05-0 Usage
Description
Raltegravir, also known as MK-0518 and marketed under the brand name Isentress, is a potent integrase inhibitor for both wild-type (WT) and S217Q PFV IN strains of HIV-1. It is the first of its class to be developed and launched as a combination treatment with other antiretroviral agents, such as NRTIs, NNRTIs, and PIs. Raltegravir works by inhibiting the essential HIV-1 integrase enzyme, which is responsible for integrating the viral DNA into the host cell's genome. This inhibition prevents the two-step process of endonucleolytic removal of the terminal dinucleotide from each 3′ end of the viral DNA and the covalent integration of the viral DNA into the host DNA, thus disrupting the viral life cycle. Raltegravir has demonstrated high selectivity and potency in vitro, with an IC50 of 2-7 nM for HIV-1 integrase strand transfer activity and a favorable safety profile.
Uses
1. Used in HIV Treatment:
Raltegravir is used as an antiretroviral agent for the treatment of HIV-1 infection. It is particularly effective against both wild-type and S217Q PFV IN strains of the virus, with IC50 values of 90 nM and 40 nM, respectively. By inhibiting the HIV-1 integrase enzyme, Raltegravir disrupts the viral life cycle and helps control the progression of the infection.
2. Used in Combination Therapy:
Raltegravir is used as a component of combination therapy with other antiretroviral agents, such as NRTIs, NNRTIs, and PIs. This approach helps to enhance the overall effectiveness of the treatment and reduce the likelihood of the virus developing resistance to the drugs.
3. Used in Research and Development:
Raltegravir is also used in research and development for the study of HIV-1 integrase and the development of new antiretroviral drugs. Its high potency and selectivity make it a valuable tool for understanding the mechanisms of HIV-1 replication and the design of novel therapeutic strategies.
Product Features
Merck's Raltegravir is the first HIV integrase strand transfer inhibitor (referred to as an integrase inhibitor). It is also known as MK-0518, which can treat human immunodeficiency virus (HIV)-1 infection combining with other antiretroviral (ARV) drugs. It slows HIV-1 infection by inhibiting the necessary HIV integrase for viral replication. When raltegravir combines with other anti-HIV drugs, it can reduce the amount of HIV in the blood, while it can increase the number of so-called CD4+ T cells that belong to white blood cells. It helps against other infections. The interaction between raltegravir and ritonavir, efavirenz, tipranavir and tenofovir indicates that there is no drug cross-resistance, and there is a synergistic effect with a variety of drugs. The most common adverse reactions are diarrhea, nausea, headache. In addition, blood tests show that the muscle enzymes abnormally increased in some of patients who taked this drug.
The above information is edited by the lookchem of Kui Ming.
Acquired resistance
Several characteristic mutations leading to typical amino
acid exchanges have been characterized in cell culture studies
and confirmed in clinical trial participants with virological
failure while receiving raltegravir in combination with
other antiretrovirals. Virological failure has generally been
associated with mutations at one of three residues – Y143,
Q148 or N155 – usually in combination with at least one
other mutation.
Pharmaceutical Applications
Formulated as the potassium salt for oral administration.
Pharmacokinetics
Oral absorption: Not known/available
Cmax 400 mg twice daily: c. 2.17 mg/L
Plasma half-life: c. 9 h
Volume of distribution: Not known/available
Plasma protein binding: c. 83%
Absorption and distribution
It may be administered without regard to food. There are few data regarding its capacity to penetrate into genital secretions or breast milk. A study of 25 HIV-infected individuals receiving raltegravir as a component of combination antiretroviral therapy found that 24 had detectable levels and that 50% of these reached a level exceeding the 95% inhibitory concentration reported to inhibit HIV-1 strains fully susceptible to integrase inhibition.
Metabolism and excretion
It is not a substrate, and does not appear to inhibit or induce the cytochrome P450 enzyme complex. It is primarily metabolized through hepatic glucuronidation mediated by the UGT-1A1 enzyme. It is excreted in the feces (51%) and the urine (32%) as unaltered compound and its glucuronide. There are no recommended dose adjustments for weight, sex and race, or for hepatic or renal insufficiency. The pharmacokinetic handling in children has not been determined.
Side effects
Its toxicity profile to date is remarkably benign. Clinical trial
participants experienced similar types and frequencies of
adverse events as those receiving placebo. The most frequently
reported adverse events were nausea, diarrhea and headache
and were mostly mild to moderate in intensity. Myopathy,
rhabdomyolysis and elevations of creatinine phosphokinase
have been noted in a few trial participants and it should be
used cautiously in combination with drugs associated with
muscle toxicity.
Synthesis
The synthesis of raltegravir begins with the treatment of acetone cyanohydrin with liquid ammonia in a pressure vessel. The resulting aminonitrile is protected as the benzyl carbamate before reaction of the nitrile moiety with hydroxylamine to afford the amidoxime. The pyrimidone ring is then constructed by condensation with dimethyl acetylenedicarboxylate and subsequent cyclization in hot xylene. Methylation of the pyrimidone is performed next with iodomethane and magnesium methoxide in dimethylsulfoxide followed by conversion of the methyl ester to an amide with 4-fluorobenzylamine. The amine, liberated from hydrogenolytic removal of the carbobenzyloxy-protecting group, is acylated with oxadiazolecarbonyl chloride, prepared in three steps from 5-methyltetrazole, to afford raltegravir.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin,
consider increasing raltegravir dose.
Antivirals: avoid with fosamprenavir.
Orlistat: absorption of raltegravir possibly reduced.
Ulcer-healing drugs: concentration increased by
omeprazole and famotidine.
Metabolism
Metabolised via glucuronidation, catalysed by the enzyme
uridine diphosphate glucuronosyltransferase.
Raltegravir is excreted in both urine and faeces as
unchanged drug and metabolites.
Check Digit Verification of cas no
The CAS Registry Mumber 518048-05-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 5,1,8,0,4 and 8 respectively; the second part has 2 digits, 0 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 518048-05:
(8*5)+(7*1)+(6*8)+(5*0)+(4*4)+(3*8)+(2*0)+(1*5)=140
140 % 10 = 0
So 518048-05-0 is a valid CAS Registry Number.
InChI:InChI=1/C20H21FN6O5/c1-10-25-26-17(32-10)16(30)24-20(2,3)19-23-13(14(28)18(31)27(19)4)15(29)22-9-11-5-7-12(21)8-6-11/h5-8,28H,9H2,1-4H3,(H,22,29)(H,24,30)
518048-05-0Relevant articles and documents
Seeking for Selectivity and Efficiency: New Approaches in the Synthesis of Raltegravir
Caputo, Francesco,Corbetta, Stefano,Piccolo, Oreste,Vigo, Daniele
, p. 1149 - 1156 (2020/07/25)
The present work describes the development of an improved synthesis of active pharmaceutical ingredient raltegravir. The isolation of a new process intermediate and the newly developed conditions solve the issue of selectivity typical of this production process, with no need for the use of protecting groups, making the present route more efficient and sustainable than what was reported before. Efficiency comparisons with the previous processes confirm the result here obtained.
A Facile Synthesis of Raltegravir Potassium—An HIV Integrase Inhibitor
Karumanchi, Kishore,Nangi, Gangadhara Bhima Shankar,Danda, Subba Reddy,Chavakula, Ramadas,Korupolu, Raghu Babu,Bonige, Kishore Babu
, p. 2683 - 2690 (2019/08/21)
A facile, cost-effective, and commercially viable synthesis of Raltegravir Potassium (1) has been developed from 2-(1-amino-1-methyl-ethyl)-N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-6-oxo-4-pyrimidinecarboxamide (9) with high purity and in good yields. In addition, a new approach for the synthesis of key amine intermediate (9) of Raltegravir Potassium (1) from commercially available 2-amino-2-methylpropanenitrile hydrochloride (2) is also described. The key features of the synthesis are fewer synthetic steps, employing the inexpensive reagents and eco-friendly.
Preparation method of pyrimidinone amide type compound
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Paragraph 0047; 0048; 0049, (2018/10/19)
The invention discloses a pyrimidinone amide type compound and a preparation method thereof. A pyrimidinone compound is taken as a starting material and is subjected to four-step chemical conversion to obtain TN-A005 and an analogue thereof, and an intermediate can be prepared from methyl tetrazole. A one-pot method is used for feeding in the whole preparation process, post-treatment purificationof each step is recrystallization or dispersion washing, the use of means such as silica gel column chromatography is avoided, the preparation technology is greatly simplified, the preparation efficiency is improved, and the total yield can reach 50%. The method is simple and convenient in preparation steps and can improve the preparation efficiency.
