1051375-16-6 Usage
Description
GSK1349572, also known as Dolutegravir, is a second-generation HIV-1 integrase strand transfer inhibitor (INSTI) with potent antiviral activity. It was discovered through rational design, replacing the monocyclic component of a literature diketo acid HIV integrase inhibitor with a tricyclic carbamoyl pyridone moiety. This modification, along with others, resulted in a compound with an IC50 of 2.7 nM, making it a highly effective inhibitor of HIV integrase. Dolutegravir is a white solid and is marketed under the brand name Tivicay.
Uses
Used in HIV/AIDS Treatment:
GSK1349572 is used as an antiretroviral medication for the treatment of HIV-1 infection in adults and children ages 12 years and older. It is administered in combination with other antiretroviral drugs to suppress the replication of the virus and manage the progression of the disease.
Used in Clinical Trials:
GSK1349572 is currently in Phase III clinical trials, further evaluating its safety and efficacy in treating HIV infection. It has demonstrated potent inhibition of HIV replication in various cell types, such as peripheral blood monuclear cells (PBMCs), MT-4 cells, and CIP4 cells infected with a self-inactivating PHIV lentiviral vector.
Used in Combating Drug Resistance:
GSK1349572 is used as a moderately effective treatment against significant HIV mutants, such as Y143R, Q148K, N155H, and G140S/Q148H, which are resistant to Raltegravir, another integrase strand transfer inhibitor. This makes it a valuable option for patients with drug-resistant strains of HIV.
Used in the Pharmaceutical Industry:
In the pharmaceutical industry, GSK1349572 is utilized as a key component in the development of new antiviral drugs targeting HIV-1. Its potent inhibitory activity and ability to overcome drug resistance make it a promising candidate for the treatment of HIV/AIDS and a valuable asset in the ongoing fight against the global epidemic.
Anti-AIDS drugs
Dolutegravir (Tivicay) was a new kind of anti-ADIS drug that jointly developed by the British pharmaceutical giant GlaxoSmithKline (GSK) with the Japanese Shionogi Pharmaceutical Company (Shionogi).
In July 2012, the GlaxoSmithKline Pharmaceuticals and Japan's Shionogi Pharmaceutical Company announced the results of Phase III clinical trial of the new AIDS drug Dolutegravir. After 48 weeks of treatment with dolutegravir and two other older versions of the AIDS drug, 88% of the virus in vivo was successfully inhibited, while the use of Gilead Sciences (Gilead Sciences) of the three-in-one oral drug Atripla (Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate), 81% of the virus in patients was inhibited, which can be seen that, the dolutegravir developed by the GlaxoSmithKline pharmaceutical companies is slightly better. According to the researchers, in a comparative trial, owing to the side effects of the drugs, 10% of the patients stopped taking the Atripla drug developed from Gilead Technologies while only 2% stopped taking GlaxoSmithKline's dolutegravir Drug, therefore, we can see that the dolutegravir drugs from GlaxoSmithKline has slightly higher safety.
On August 12, 2013, the US Food and Drug Administration (FDA) approved the use of dolutegravir for being used in previously treated or early treated HIV-1 adults and 12 years of age and above infected children of at least 40 kg.
Dolutegravir is a once-daily drug with its efficacy being comparable to Merck's HIV/AIDS drug Raltegravir (Isentress) in Phase III clinical trials. Raltegravir should be subject to daily administration twice. Both of them are inhibitors of HIV integrase. The FDA official claim that the AIDS patient should be subject to targeted treatment on a case-by-case basis. Tivicay will provide patients with new options. In a study done a year ago, 88% of patients had a significant improvement after 48 weeks of Tivicay treatment, better than the efficacy of the Gilead's Atripla. Analysts expect that Dolutegravir will become a multi-billion-dollar blockbuster drug and a strong contender for Atripla, the world's best-selling HIV drug, developed by Gilead Sciences.
Common name: Dolutegravir
Trade name: Tivicay
Alias: GSK1349572, S-349572, GSK572
Drug Company: GlaxoSmithKline
Indications: AIDS
Drug type: integrase inhibitors
Approved date: August 12, 2013 (US)
CAS Registry Number: 1051375-16-6
Chemical name: (4R, 12aS)-N-[(2, 4-difluorophenyl) methyl]-3, 4, 6, 8, 12, 12a-hexahydro-7-hydroxy-Dioxo-2H-pyrido [1 ', 2': 4,5] pyrazino [2,1-b] [1,3] oxazine-9-carboxamide
U.S. Patent No. 8,129,385
The patent expires on October 5, 2027
International patent: W02006116764
This information is compiled and edited by Xiao Nan of lookchem.
Originator
Shionogi & GlaxoSmithKline (United States)
Clinical Use
Integrase inhibitor:Treatment of HIV
Drug interactions
Potentially hazardous interactions with other drugsAntidepressants: concentration reduced by St John’s
wort.Antiepileptics: concentration reduced by
carbamazepine and possibly fosphenytoin,
oxcarbazepine, phenobarbital, phenytoin and
primidone.Antivirals: concentration reduced by efavirenz,
tipranavir, etravirine and fosamprenavir; possibly
reduced by nevirapine.
Metabolism
Dolutegravir is primarily metabolised through
glucuronidation via UGT1A1 with a minor CYP3A
component.53% of the total oral dose is excreted unchanged in
the faeces. It is unknown if all or part of this is due to
unabsorbed active substance or biliary excretion of the
glucuronidate conjugate, which can be further degraded to
form the parent compound in the gut lumen.
Check Digit Verification of cas no
The CAS Registry Mumber 1051375-16-6 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,0,5,1,3,7 and 5 respectively; the second part has 2 digits, 1 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 1051375-16:
(9*1)+(8*0)+(7*5)+(6*1)+(5*3)+(4*7)+(3*5)+(2*1)+(1*6)=116
116 % 10 = 6
So 1051375-16-6 is a valid CAS Registry Number.
1051375-16-6Relevant articles and documents
7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir
Ziegler, Robert E.,Desai, Bimbisar K.,Jee, Jo-Ann,Gupton, B. Frank,Roper, Thomas D.,Jamison, Timothy F.
, p. 7181 - 7185 (2018)
Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available materials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one-step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.
Identification and Control of Critical Process Impurities: An Improved Process for the Preparation of Dolutegravir Sodium
Sankareswaran, Srimurugan,Mannam, Madhavarao,Chakka, Veerababu,Mandapati, Srirami Reddy,Kumar, Pramod
, p. 1461 - 1468 (2016)
A four-stage manufacturing route for the preparation of dolutegravir sodium (1) was assessed and optimized leading to a higher yielding, simpler and scalable process. Key improvements in the process include the development of mild workup procedure by selective derivatization of a difficult to remove a process impurity using tert-butyldimethylsilyl chloride. Metal-based hydrogenation-free O-debenzylation is optimized, and the critical isomeric impurity formed was identified and eliminated from the process by the establishment of a proper control strategy.
Synthesis of two diastereomeric impurities of a fluorinated antiretroviral drug dolutegravir
Amasa, Srinivasulu Reddy,Garrepalli, Sailaja,Gudipati, Ramesh,Pal, Manojit,Ravindhranath, Kunta
, (2022/01/10)
The study of drug impurities constitutes an important area of process research and development. In the current study the synthesis of two diastereomeric impurities namely R,R- and S,S-isomer of recently approved antiretroviral drug dolutegravir was explored. Accordingly, a simple and scalable process has been developed for the first time for the synthesis of said impurities starting from a common intermediate, e.g. ethyl 5-((2,4-difluorobenzyl)carbamoyl)-3-ethoxy-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate. The methodology involved individual treatment of this common ester with (S)- and (R)-3-amino-1-butanol separately to afford the corresponding target compound in good yield. The IR, 1H, 13C and 19F NMR and Mass spectral data as well as HPLC and HRMS analysis were used to characterize the synthesized impurities. Both the impurities were prepared in gram scale suggesting scale-up potential of the methodology developed. Besides being economical as well as free from the use of expensive catalyst, the methodology involved the use of mild reaction conditions and workup procedure. Additionally, the reaction conditions adopted in the current approach are suitable for the laboratory as well as industrial applications. The current study would be of considerable interest to researchers engaged in the process development for accessing chemically pure dolutegravir.
Method for synthesizing diastereomer impurity in dolutegravir raw material
-
, (2019/11/13)
The invention provides a method for synthesizing a diastereomer impurity in a dolutegravir raw material, which comprises the following steps: 1, carrying out condensation reaction on SM1 serving as araw material and 2,4-difluorobenzylamine to generate a compound I; 2, reacting the compound I with an alkali in a reaction solvent to generate a compound II; 3, hydrolyzing the compound II under an acidic condition to generate a compound III; 4, carrying out acid catalytic reaction on the compound III and R-aminobutanol in a reaction solvent to generate a compound IV; 5, generating a compound V from the compound IV in a reaction solvent under the catalysis of a condensing agent; and 6, demethylating the compound V under the action of an alkali metal salt to generate an impurity VI. The synthetic method of the diastereoisomer impurity in the dolutegravir raw material is simple in process and available in raw material, and the prepared new impurity can provide a reference substance for quality analysis of dolutegravir, so that the quality standard of dolutegravir is improved.
