134678-17-4 Usage
Description
Lamivudine is a new generation orally active nucleoside analog launched in the U.S.A. for use in combination with zidovudine (AZT) as a first-line therapy for patients with HIV infection. Lamivudine is rapidly converted to phosphorylated metabolites in the body which act as inhibitors and chain terminators of HIV reverse transcriptase (RT), the enzyme required for the replication of the HIV genome. Lamivudine has similar inhibitory potency to RT as AZT but is 10 times less toxic and is active against AZT-resistant strains of HIV.
Chemical Properties
White Crystalline Powder
Originator
BioChem Pharma (Canada)
Uses
Lamivudine is used along with other medications to treat human immunodeficiency virus (HIV) infection in adults and children 3 months of age and older. Lamivudine (Epivir-HBV) is used to treat hepatitis B infection. Lamivudine is in a class of medications called nucleoside reverse transcriptase inhibitors (NRTIs). It works by decreasing the amount of HIV and hepatitis B in the blood.
Synthesis
Aqueous hydrochloric acid (6N, 30 ml) was slowly added to a solution of 20 gm of the solid (2R-cis)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidi- none.S-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate in water (200 ml) at 45-50 deg C. Stirred the reaction for 1 hour at room temperature. The solid S-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate was filtered and the aqueous layer was neutralized with aqueous sodium hydroxide solution (30%, 20 ml). The solvent was recovered under vacuum at 40-45 deg C., the product obtained was dissolved in methanol (200 ml), filtered to remove the inorganic salts, the filtrate was concentrated under vacuum at 40-45 deg C. and the residual solid obtained was dissolved in ethanol (50 ml), heated to 50 deg C., slowly allowed to room temperature, cooled to 10 deg C., filtered and dried at 40-45 deg C. to obtain 5 gm of Lamivudine(Chiral purity: 97.5%).
Definition
ChEBI: Lamivudine is a monothioacetal that consists of cytosine having a (2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl moiety attached at position 1. An inhibitor of HIV-1 reverse transcriptase.
Brand name
Epivir (GlaxoSmithKline).
Acquired resistance
Long-term lamivudine administration frequently elicits viral resistance characterized by a reincrease of viral replication in an adherent patient. The incidence of lamivudine resistance is 14% to 32% after 1 year of treatment, 38% after 2 years, and 53% to 76% after 3 years.
Pharmaceutical Applications
An analog of cytidine available for oral administration.
Pharmacokinetics
The pharmacokinetics of lamivudine are similar in patients with HIV-1 or HBV infection, and healthy volunteers. The drug is rapidly absorbed after oral administration, with maximum serum concentrations usually attained 0.5 to 1.5 hours after the dose.
Clinical Use
Lamivudine is indicated for the treatment of HIV when
used in combination with other antiretroviral agents.A
lower dose than that used to treat HIV is approved for
the treatment of HBV.
Side effects
Lamivudine oral tablet can cause mild or serious side effects. The more common side effects that can occur with lamivudine include:cough,diarrhea,fatigue,headache,malaise (general discomfort),nasal symptoms, such as a runny nose,nausea.
Drug interactions
There are potentially dangerous interactions with other drugs when used in combination.Antimicrobials: trimethoprim inhibits the excretion of lamivudine.Antivirals: avoid concomitant use with foscarnet, emtricitabine, and IV ganciclovirCytotoxic drugs: avoid concomitant use with clarithromycin.Orlistat: absorption may be reduced by orlistat.
Metabolism
Lamivudine is metabolised intracellularly to the active antiviral triphosphate. Hepatic metabolism is low (5-10%) and the majority of lamivudine is excreted unchanged in the urine via glomerular filtration and active secretion (organic cationic transport system).
References
Arts and Wainberg (1996), Mechanism of nucleoside analog antiviral activity and resistance during human immunodeficiency virus reverse transcription; Antimicrob. Agents Chemother., 40 527
Coates et al. (1992), (-)-2’-deoxy-3’-thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro; Antimicrob. Agents Chemother., 36 733
Kong et al. (2022), Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy; Cell Death Dis., 13 336
Rajukar et al. (2022), Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer; Cancer Discov., 2021 Online ahead of print
Check Digit Verification of cas no
The CAS Registry Mumber 134678-17-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,4,6,7 and 8 respectively; the second part has 2 digits, 1 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 134678-17:
(8*1)+(7*3)+(6*4)+(5*6)+(4*7)+(3*8)+(2*1)+(1*7)=144
144 % 10 = 4
So 134678-17-4 is a valid CAS Registry Number.
InChI:InChI=1/C8H11N3O3S/c9-5-1-2-11(8(13)10-5)6-4-15-7(3-12)14-6/h1-2,6-7,12H,3-4H2,(H2,9,10,13)/t6-,7+/m1/s1
134678-17-4Relevant articles and documents
The chemical resolution of racemic CIS-2-hydroxymethyl-5-(Cytosine-1′-YL)-1,3-oxathiolane (BCH-189) - One direct method to obtain lamivudine as anti-HIV and anti-HBV agent
Li, Ji-zhen,Gao, Lian-xun,Ding, Meng-xian
, p. 2355 - 2359 (2002)
Racemic cis-BCH-189 can be resolved to (-)-enantiomer (lamivudine) and (+)-enantiomer by esterification of cis-2-hydroxymethyl-5-(N′4-acetylcyto sine-1′-yl)-1,3-oxathiolane and (+)-menthyl chloroformate in CH3CN with pyridine as base. The two diastereomers of ester were seperated by recrystallization in methanol at 0°C. Lamivudine was obtained by deprotection of (-)-diastereomer with high yield.
An Economical Route to Lamivudine Featuring a Novel Strategy for Stereospecific Assembly
Abdiaj, Irini,Ahmad, Saeed,Burns, Justina M.,Gopalsamuthiram, Vijayagopal,Gupton, B. Frank,Krack, Rudy,McQuade, D. Tyler,Nelson, Ryan C.,Snead, David R.,Stringham, Rodger W.
, p. 1194 - 1198 (2020)
An economical synthesis of lamivudine was developed by employing a new method to establish the stereochemistry about the heterocyclic oxathiolane ring. Toward this end, an inexpensive and readily accessible lactic acid derivative served the dual purpose of activating the carbohydrate's anomeric center for N-glycosylation and transferring stereochemical information to the substrate simultaneously. Both enantiomers of the lactic acid derivative are available, and either β-enantiomer in this challenging class of 2′-deoxynucleoside active pharmaceutical ingredients can be formed.
Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint-Driven Innovation
Burns, Justina M.,Gupton, B. Frank,Kashinath, K.,McQuade, D. Tyler,Snead, David R.,Stringham, Rodger W.
, p. 2266 - 2270 (2020)
A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low-cost, widely available starting materials - we refer to this as supply-centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precursors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate, and water to produce the oxathiolane.
Multienzymatic cascade synthesis of an enantiopure (2R,5R)-1,3-oxathiolane anti-HIV agent precursor
Ren, Yansong,Hu, Lei,Ramstr?m, Olof
, p. 52 - 56 (2019/02/24)
An enantiopure (2R,5R)-1,3-oxathiolane was obtained using a multienzymatic cascade protocol. By employing a combination of surfactant-treated subtilisin Carlsberg and Candida antarctica lipase B, the absolute configuration of the resulting 1,3-oxathiolane ring was efficiently controlled, resulting in an excellent enantiomeric excess (>99%). This enantiopure 1,3-oxathiolane derivative is a key precursor to anti-HIV agents, such as lamivudine, through subsequent N-glycosylation.