139110-80-8 Usage
Description
Zanamivir Hydrate, also known as Relenza, is a potent and specific inhibitor of neuraminidase (or sialidase), a key viral surface glycohydrolase essential for viral replication and disease progression by catalyzing the cleavage of terminal sialic acid residues from the glycoprotein. It is a sialic acid analog that possesses a guanidino group at position 4 instead of a hydroxyl group, which allows it to form a salt bridge with the guanidine and Glu-119 and a charge transfer interaction with Glu-227. These interactions increase the interaction strength with the enzyme, making it an excellent competitive inhibitor and an effective antiviral agent for influenza types A and B.
Uses
Used in Pharmaceutical Industry:
Zanamivir Hydrate is used as an antiviral agent for the treatment of human influenza A and B virus infections. It is particularly effective when administered before or after exposure to the influenza virus. If administered before exposure, the drug reduces viral propagation, infectivity, and disease symptoms. If administered after exposure, the drug reduces propagation, viral titer, and illness. Zanamivir Hydrate is marketed as a dry powder for oral inhalation and is used in adolescents and adults who have been exposed and are symptomatic for not more than 2 days. It is also indicated for prophylactically treating family members of a person who has developed influenza.
Additionally, Zanamivir Hydrate is used as an anti-neoplastic and anti-metabolite agent, potentially offering therapeutic benefits in cancer treatment. Its in vitro activity against a wide variety of influenza A and B strains demonstrates its superior effectiveness compared to other antiviral agents like amantadine and rimantadine.
Originator
Biota Scientific
Management (Australia)
Indications
Zanamivir (Relenza) is a neuraminidase inhibitor with
activity against influenza A and B strains. Like oseltamivir,
zanamivir is a reversible competitive antagonist
of viral neuraminidase. It inhibits the release of
progeny virus, causes viral aggregation at the cell surface,
and impairs viral movement through respiratory
secretions. Resistant variants with hemagglutinin and/or
neuraminidase mutations have been produced in vivo;
however, clinical resistance to zanamivir is quite rare at
present.
Manufacturing Process
The 1st method of preparation of zanamivir:5-(Acetylamino)-4-amino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-
non-2-enonic acid (3 g, 10.35 mmol) was suspended in methanol (37.5 ml)
and sodium acetate (1.89 g, 23.1 mmol) was added, causing a "caking" of the
suspension and making stirring difficult. To this at 21°C with exclusion of
moisture was added a solution of cyanogen bromide (1.14 g, 10.8 mmol) in
methanol (150 ml), in a dropwise manner. Stirring gradually became easier,
until a readily stirrable suspension was obtained. Addition was complete in 3.5
hours. The mixture was then stirred at 21°C with exclusion of moisture for 44
hours. The small amount of remaining solid was filtered off and solvent
evaporated in vacuo to an orange-brown foam. The foam was taken up in
methanol (125 ml) and with rapid stirring at 21°C was treated dropwise with
propan-2-ol (130 ml). The precipitate was filtered off, washed with iso-
PrOH/MeOH (3:2), and combined filtrate and washings evaporated to give the
5-(acetylamino)-4-cyanoamino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-
galacto-non-2-enonic acid as a pale yellow foam (3.48 g).5-(Acetylamino)-4-cyanoamino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-
galacto-non-2-enonic acid (500 mg, 1.59 mmol) was dissolved in dried (over
3 A mol. sieves) methanol (20 ml) and anhydrous hydrazine (0.5 ml, 15.9
mmol) was added. This was then stirred at 21°C for 18 hours. The white
precipitate was filtered off, washed with methanol and air-dried (0.172 g,
31%). The solid was taken up in water (3.2 ml) and with warming and
swirling, propan-2-ol (8.1 ml) was added. The cystallised material was filtered
off, air-dried then dried under high vacuum to give D-glycero-D-galacto-non-
2-enonic acid, 5-(acetylamino)-4-(aminoiminomethyl)amino)-2,6-anhydro-
3,4,5-trideoxy as a white solid (0.127 g,); >97% purity; M.P. >180°C.The 2nd method of preparation of zanamivir:5-(Acetylamino)-4-cyanoamino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-
galacto-non-2-enopyranosonic acid (500 mg, 1.585 mmol) was dissolved in
dried (over 3 A mol. sieves) methanol (12 ml) and methylamine (33 wt. %
solution in ethanol, 1.93 ml, 15.85 mmol) was added. This was stirred at
21°C for 18 hours. The precipitate was filtered off and air dried to a white
solid (127 mg, 23%). This was recrystalIised from water (1.4 ml) and propan-
2-ol (6.9 ml). The product was filtered off and dried under high vacuum to
give the title compound as a white solid (56 mg, 10.2%). Concentration of
mother liquors gave a further 21.3 mg (4%) of D-glycero-D-galacto-non-2-
enonic acid, 5-(acetylamino)-4-(aminoiminomethyl)amino)-2,6-anhydro-3,4,5-
trideoxy-; 97.7% purity; M.P. >180°C.
Therapeutic Function
Antiviral
Acquired resistance
Resistance is presently uncommon, including strains resistant
to oseltamivir. In clinical trials the frequency was no more
than 1% of exposed patients.
Pharmaceutical Applications
A synthetic neuraminidase inhibitor formulated for administration
by inhalation.
Biochem/physiol Actions
Zanamivir is an influenza viral neuraminidase inhibitor.
Pharmacology
Zanamivir is generally well tolerated. Bronchospasm
and impaired lung function have been reported in some
patients taking this medication, but many of these individuals
had serious underlying pulmonary disease.
Zanamivir should be discontinued if an individual develops
bronchospasm or breathing difficulties; treatment
and hospitalization may be required. Allergic reactions,
including angioedema, have been rarely
reported. The efficacy of zanamivir depends upon the
proper use of the inhaler device.
Pharmacokinetics
Oral bioavailability is poor. After inhalation local respiratory
mucosal concentrations greatly exceed those that are inhibitory
for influenza A and B replication. The median concentrations
in the sputum exceed 1 mg/L 6 h after inhalation and
remain detectable for 24 h.
Clinical Use
Treatment of influenza A and B infections in patients over 7 years of age,
and prophylaxis of patients ??5 years of age
Clinical Use
Zanamivir is indicated for treatment of uncomplicated
acute influenza A and B virus in patients aged 7 and
older.Treatment should be initiated no later than 2 days
after the onset of symptoms. Zanamivir shortens the duration
of illness by 1 to 1.5 days. It is also an effective
prophylaxis against influenza; however, the FDA has
not approved this indication at the time of publication.
Side effects
Most adverse effects are related to the respiratory tree. These
include rhinorrhea and, rarely, bronchospasm. Nausea and
vomiting have been reported at low incidence.
Side effects
Zanamivir is contraindicated in individuals with severe
or decompensated chronic obstructive lung disease
or asthma because it has not been shown to be effective
in these individuals and can cause serious adverse pulmonary
reactions. Individuals with mild to moderate
asthma may have a decline in lung function when taking
zanamivir. The safety and efficacy of this medication
have not been determined in individuals with severe renal
insufficiency. No clinically significant drug interactions
have been reported. Zanamivir does not decrease
the effectiveness of the influenza vaccine.
Drug interactions
Potentially hazardous interactions with other drugs
None known
Metabolism
Zanamirvir is effective when administered via the nasal, intraperitoneal, and intravenous (IV) routes, but it is inactive when given orally. Animal studies have shown 68% recovery of the drug in the urine following intraperitoneal administration, 43% urinary recovery following nasal administration, and only 3% urinary recovery following oral administration. Human data gave results similar to those obtained in animal models. Human efficacy studies with nasal drops or sprays demonstrated that the drug was effective when administered before and after exposure to influenza A or B virus. When given before viral inoculation, the drug reduced viral shedding, infection, and symptoms. When administered beginning at either 26 or 32 hours after inoculation, there was a reduction in shedding, viral titer, and fever.
references
[1] elliott m. zanamivir: from drug design to the clinic. philos trans r soc lond b biol sci, 2001, 356(1416): 1885-93.
Check Digit Verification of cas no
The CAS Registry Mumber 139110-80-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,9,1,1 and 0 respectively; the second part has 2 digits, 8 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 139110-80:
(8*1)+(7*3)+(6*9)+(5*1)+(4*1)+(3*0)+(2*8)+(1*0)=108
108 % 10 = 8
So 139110-80-8 is a valid CAS Registry Number.
InChI:InChI=1/C12H20N4O7.H2O/c1-4(18)15-8-5(16-12(13)14)2-7(11(21)22)23-10(8)9(20)6(19)3-17;/h2,5-6,8-10,17,19-20H,3H2,1H3,(H,15,18)(H,21,22)(H4,13,14,16);1H2/t5-,6+,8+,9+,10+;/m0./s1
139110-80-8Relevant articles and documents
Organocatalytic and scalable synthesis of the anti-influenza drugs zanamivir, laninamivir, and CS-8958
Tian, Junshan,Zhong, Jiankang,Li, Yunsheng,Ma, Dawei
, p. 13885 - 13888 (2014)
Zanamivir, laninamivir, and CS-8958 are three neuraminidase inhibitors that have been clinically used to combat influenza. We report herein a novel organocatalytic route for preparing these agents. Only 13 steps are needed for the assembly of zanamivir and laninamivir from inexpensive d-araboascorbic acid by this synthetic route, which relies heavily on a thiourea-catalyzed enantioselective Michael addition of acetone to tert-butyl (2-nitrovinyl)carbamate and an anti-selective Henry reaction of the resulting Michael adduct with an aldehyde prepared from d-araboascorbic acid. The synthetic procedures are scalable, as evident from the preparation of more than 3.5 g of zanamivir.
Preparation method of zanamivir intermediate and preparation method of zanamivir
-
, (2017/08/02)
The invention relates to a preparation method of a zanamivir intermediate, namely an acetylation protected amino compound, and a preparation method of zanamivir. The preparation method of the zanamivir, provided by the invention, comprises the following steps: performing cyclization by taking sialic acid as a raw material and through group protection to produce a cyclization substance, treating the cyclization substance by a metal amino substance at one step to obtain the acetylation protected amino compound, and removing a hydroxyl protective agent acetic acid ester and removing guanidyl from imipyrozole reaction to obtain the zanamivir, wherein the process of treating the cyclization substance by the metal amino substance at one step to obtain the acetylation protected amino compound is great substantial breakthrough in preparation of the zanamivir, the synthesis steps are greatly shortened and the process operation is simplified. Ring opening is conducted by the cheap metal amino substance instead of expensive trimethylsilyl azid, so that the cost is reduced and the safety of the production process is guaranteed. According to thepreparation method of the zanamivir, provided by the invention, the total mass yield can reach 50 percent or above and is greatly increased as compared with that in the prior art.
Chemical insight into the emergence of influenza virus strains that are resistant to Relenza
Shidmoossavee, Fahimeh S.,Watson, Jacqueline N.,Bennet, Andrew J.
supporting information, p. 13254 - 13257 (2013/09/24)
A reagent panel containing ten 4-substituted 4-nitrophenyl α-d-sialosides and a second panel of the corresponding sialic acid glycals were synthesized and used to probe the inhibition mechanism for two neuraminidases, the N2 enzyme from influenza type A virus and the enzyme from Micromonospora viridifaciens. For the viral enzyme the logarithm of the inhibition constant (Ki) correlated with neither the logarithm of the catalytic efficiency (kcat/Km) nor catalytic proficiency (kcat/Kmkun). These linear free energy relationship data support the notion that these inhibitors, which include the therapeutic agent Relenza, are not transition state mimics for the enzyme-catalyzed hydrolysis reaction. Moreover, for the influenza enzyme, a correlation (slope, 0.80 ± 0.08) is observed between the logarithms of the inhibition (Ki) and Michaelis (Km) constants. We conclude that the free energy for Relenza binding to the influenza enzyme mimics the enzyme-substrate interactions at the Michaelis complex. Thus, an influenza mutational response to a 4-substituted sialic acid glycal inhibitor can weaken the interactions between the inhibitor and the viral neuraminidase without a concomitant decrease in free energy of binding for the substrate at the enzyme-catalyzed hydrolysis transition state. The current findings make it clear that new structural motifs and/or substitution patterns need to be developed in the search for a bona fide influenza viral neuraminidase transition state analogue inhibitor.
