Information of Remdesivir Drug. Remdesivir antiviral drug, GS-441524, valkury, Gilead science, Best drug for COVID-19 (SARS COV-2) , RNA inhibiter drug , Emergency approved by FDA. GS-5734. Made from Ribose synthesis.

1. DISSERTATION REPORT-MONOGRAPH(REMDESIVIR)
(PRESENTATION)
PRESENT BY
NAME – BHARGAV SARDHARA
ROLL NO - 9 (HPP)
M.Sc. ( ORGANIC CHEMISTRY)
SEMESTER -4
SUBMITTED TO: DR. H.D.PATEL SIR

2. WHAT IS REMDESIVIR?
• GENERIC NAME: REMDESIVIR
• ALTERNATE NAME: VALKURY
• Remdesivir (GS-5734) was developed by Gilead Sciences and emerged from a collaboration
between Gilead, the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. Army
Medical Research Institute of Infectious Diseases (USAMRIID).
• They sought to identify therapeutic agents for treating RNA-based viruses that maintained
global pandemic potential, such as those that indeed emerged following the initiation of the
program, including EBOV and the Coronaviridae family viruses exemplified by Middle East
respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS)
• Remdesivir is an investigational new drug created by Gilead. The research that led to
remdesivir began as early as 2009, with research programs under way in hepatitis C (HCV) and
respiratory syncytial virus (RSV).
• We continued to explore various uses for remdesivir following its discovery, including antiviral
profiling in 2013 and early 2014 that suggested the potential for remdesivir to have broad
spectrum antiviral activity.

3. Class: Nucleosides and Nucleotides
Chemical Name: 2-Ethylbutyl N-{(S)-[2-C-(4-
aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-
anhydro-d-altrononitril-6-O-yl]
phenoxyphosphoryl}-L-alaninate
Molecular Formula: C27H35N6O8P
Introduction: Antiviral; nucleoside RNA
polymerase inhibitor.
How is remdesivir given to COVID-19 patients?
The drug is given intravenously to hospitalized
patients with COVID-19. People typically
receive an injection once a day for 5 to 10 days,
based on the severity of their condition.

4. DOSAGE:
• Remdesivir is indicated for the treatment of adult and pediatric patients aged 12 years
and over weighing at least 40 kg for coronavirus disease 2019 (COVID-19) infection
requiring hospitalization.
• Pediatric Patients ≥12 Years of Age Weighing ≥40 kg
• Hospitalized, not requiring invasive mechanical ventilation and/or ECMO: Loading dose
of 200 mg by IV infusion on day 1, followed by maintenance doses of 100 mg by IV
infusion once daily starting on day 2. Recommended total treatment duration is 5 days.
If no clinical improvement, may continue at a dosage of 100 mg by IV infusion once
daily for up to 5 additional days.
• Pediatric Patients Weighing 3.5 to <40 kg
• Hospitalized, not requiring invasive mechanical ventilation and/or ECMO: Loading dose
of 5 mg/kg by IV infusion on day 1, followed by maintenance doses of 2.5 mg/kg by IV
infusion once daily starting on day 2. Recommended total treatment duration is 5 days.
If no clinical improvement, may continue at a dosage of 2.5 mg/kg by IV infusion once
daily for up to 5 additional days.

5. Eligible Patients for REMDESIVIR
• Eligible patients were men and non-pregnant women with COVID-19
who were aged at least 18 years and were RT-PCR positive for SARS-
CoV-2, had pneumonia confirmed by chest imaging, had oxygen
saturation of 94% or lower on room air or a ratio of arterial oxygen
partial pressure to fractional inspired oxygen of 300 mm Hg or less,
and were within 12 days of symptom onset.
• Eligible patients of child-bearing age (men and women) agreed to
take effective contraceptive measures (including hormonal
contraception, barrier methods, or abstinence) during the study
period and for at least 7 days after the last study drug administration.

6. WHY DEVELOP ?
 Developing such antiviral drugs is an exacting task, for a few reasons.
 Once a virus has entered a cell, it depends on the cell’s machinery to replicate, unlike many
most bacteria. So drugs designed to target the virus could have detrimental effects on the
host cells as well.
 Second, continuous use of antiviral drugs could aggravate the selective pressure on the
viruses. That is, after being repeatedly exposed to the same drug, viruses could begin to
mutate towards becoming drug-resistant. And the drug may not work as effectively against
new strains of the same virus.
• The remdesivir formulations contain the excipient sulfobutylether-beta-cyclodextrin
(SBECD), with the injection solution containing 6 g per 100 mg remdesivir and the
lyophilized powder containing 3 g per 100 mg remdesivir. SBECD accumulates in patients
with kidney dysfunction, although the clinical significance of this accumulation is not
certain. SBECD is dialyzable (46% removed by an ~4-hour dialysis session)

7. ADVERSE REACTION:
• Very common (10% or more): Increased transaminases, increased ALT, increased AST
• Common (1% to 10%): Increased aminotransferase levels (including ALT, AST, or both),
increased bilirubin
• Uncommon (0.1% to 1%): Increased hepatic enzyme, hypertransaminasemia, increased liver
function tests.
• Side effects include: Adverse effects reported in ≥5% of patients receiving remdesivir
include nausea and increased ALT and AST concentrations.
• General: The most common side effect in healthy subjects was increased transaminases. The
most common side effects in patients with coronavirus disease 2019 (COVID-19) were
nausea, increased AST, and increased ALT.
• Mild: Diaphoresis, Diarrhea, Ecchymosis, Fever, Headache, injection site reaction,
musculoskeletal pain, Nausea, rash.

8. Mechanism of action:
• Remdesivir is an adenosine nucleotide prodrug that is metabolized within host cells to form the
pharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as
an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for
incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase,
which results in delayed chain termination during replication of the viral RNA.
• Absorption: Remdesivir is absorbed quickly; maximal plasma concentrations following a
single 30-minute intravenous infusion are reached within 0.67-0.68 hours.
• Metabolism: Remdesivir is a phosphoramidate prodrug that must be metabolized
within host cells to its triphosphate metabolite to be therapeutically active. Upon cell
entry, remdesivir is presumed to undergo first esterase-mediated hydrolysis to a
carboxylate form followed by cyclization to eject the phenoxide moiety and finally
hydrolysis of the cyclic anhydride to yield the detectable alanine metabolite.

9. • Solubility: Remdesivir is very slightly soluble (0.35 mg/mL) at pH 2, practically insoluble (0.04
mg/mL) at pH 4, and practically insoluble (0.03 mg/mL) at pH 7. The partition coefficient (log
P) is 3.2 and the pKa is 3.3.
How is remdesivir given?
• Your doctor will perform blood tests to make sure you do not have conditions that would
prevent you from safely using remdesivir. Remdesivir is given as an infusion into a vein. A
healthcare provider will give you this injection. remdesivir must be given slowly, and the
infusion can take 30 to 120 minutes to complete. Remdesivir is usually given once per day for
5 to 10 days. You will need frequent blood tests to check your liver function. You must remain
under the care of a doctor while you are being treated with remdesivir for COVID-19.
How does remdesivir help patients with COVID-19?
• The drug prevents the virus from producing a particular enzyme that is necessary for the virus
to replicate itself. Once this happens, the virus is no longer able to spread within the body.

10. Procedure:
Remdesivir can be synthesized in multiple steps from ribose derivatives.
 In this method, intermediate a is firstly prepared from L-alanine and phenyl
phosphor dichloridate in presence of triethylamine and dichloromethane;
 triple benzyl-protected ribose is oxidized by dimethyl sulfoxide with acetic
anhydride and give the lactone intermediate b;
 pyrrol[2,1-f] [1,2,4]triazin-4-amine is brominated, and the amine group is protected
by excess trimethylsilyl chloride. n-Butyllithium undergoes a halogen-lithium
exchange reaction with the bromide at −78 °C (−108 °F) to yield the intermediate c.
 The intermediate b is then added to a solution containing intermediate c dropwise.
 After quenching the reaction in a weakly acidic aqueous solution, a mixture of
1:1 anomers was obtained.

11. Continue:
 It was then reacted with an excess of trimethylsilyl cyanide in dichloromethane at
−78 °C (−108 °F) for 10 minutes. Trimethylsilyl triflate was added and reacts for one
additional hour, and the mixture was quenched in an aqueous sodium hydrogen
carbonate. A nitrile intermediate was obtained.
 The protective group, benzyl, was then removed with boron trichloride in
dichloromethane at −20 °C (−4 °F).
 The excess of boron trichloride was quenched in a mixture of potassium carbonate
and methanol. A benzyl-free intermediate was obtained.
 The isomers were then separated via reversed-phase HPLC. The optically pure
compound and intermediate a are reacted with trimethyl phosphate and
methylimidazole to obtain a diastereomer mixture of remdesivir.
 In the end, optically pure remdesivir can be obtained through chiral
resolution methods.

12. Reaction:

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