1051375-16-6 Usage
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.
Uses
Different sources of media describe the Uses of 1051375-16-6 differently. You can refer to the following data:
1. Dolutegravir (GSK1349572) is a HIV integrase inhibitor with an IC50 of 2.7 nM and is moderately effective against the significant mutants Y143R, Q148K, N155H, and G140S/Q148H against Raltegravir.
2. Dolutegravir is a second generation HIV-1 integrase strand transfer inhibitor. Dolutegravir is currently in Phase III clinical trials for the treatment of HIV infection. Dolutegravir has been shown to potently inhibit HIV replication in cells such as peripheral blood mononuclear cells (PBMCs), MT-4 cells and CIP4 cells infected with a self-inactivating PHIV lentiviral vector.
3. Dolutegravir is a second generation HIV-1 integrase strand transfer inhibitor. Dolutegravir is currently in Phase III clinical trials for the treatment of HIV infection. Dolutegravir has been shown to
potently inhibit HIV replication in cells such as peripheral blood mononuclear cells (PBMCs), MT-4 cells and CIP4 cells infected with a self-inactivating PHIV lentiviral vector.
Description
In August 2013, the US FDA approved dolutegravir (also referred to as S/GSK1349572) for the treatment of HIV-1 infection in adults and children ages 12 years and older in combination with other antiretroviral drugs. Dolutegravir was approved in Canada in November 2013. HIV/AIDS remains a global epidemic with 35 million people infected, including 2.3 million new infections as of 2012. Dolutegravir joins raltegravir and elvitegravir (this chapter of ARMC) as the latest of three FDA-approved HIV integrase strand transfer inhibitors (INSTIs). Dolutegravir was discovered by rational design from a literature diketo acid HIV integrase inhibitor utilizing X-ray coordinates to predict ideal bond angles between the diketone and distal benzyl group. In dolutegravir, the monocyclic component of the reported inhibitor was replaced with the tricyclic carbamoyl pyridone moiety. The researchers postulated that the appropriate arrangement of three oxygens would permit chelation with two magnesium ions in the binding site thus affording improved potency. Ultimately, this arrangement along with further modifications afforded dolutegravir, a potent inhibitor of HIV integrase (IC50=1.7 nM).
Chemical Properties
White Solid
Originator
Shionogi & GlaxoSmithKline (United States)
Definition
ChEBI: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of (4R,12aS)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]ox
zine-9-carboxylic acid with the amino group of 2,4-difluorobenzylamine. Used (as its sodium salt) for treatment of HIV-1.
Brand name
Tivicay
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.
CONTINUES FLOW PROCESS FOR THE PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS - POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVES AND INTERMEDIATES THEREOF
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Page/Page column 34; 35; 36; 38; 39, (2019/09/04)
The present invention discloses continues flow process for the preparation of polycyclic carbamoyl pyridone derivatives and intermediates thereof. In particular, the present invention discloses a process for the preparation of intermediate. Formule (V).
