Tamiflu

Although oseltamivir (1, Tamiflu) has risen to be a superstar in the wake of the avian flu, zanamivir (2, Relenza) seems to be underappreciated by the world medical society, possibly because zanamivir (2) is a mouth spray and may cause problems for patients with breathing problems such as asthma. In reahty, zanamivir (2) has a great tolerability, similar to that of placebo, for otherwise healthy adults and higher-risk patients such as the elderly and children. Recommended doses (10 mg twice daily for 5 days) of zanamivir (2) did not adversely affect pulmonary function in patients with respiratory disorders in a well-controlled trial, although there have been reports of bronchospasm and/or decline in respiratory function. 

Zanamivir (2) is a potent competitive inhibitor of viral neuraminidase glycoprotein, which is essential in the infective cycle of both influenza A and B viruses. It inhibits a wide range of influenza A and B types in vitro as well as in vivo. The concentrations of inhibiting in vitro plaque formation of influenza A and B virus by 50% in Madin-Darby canine kidney (MDCK) cells were 0.004-0.014 p.mol/L in laboratory-passaged strains, and 0.002-16 p.mol/L in assays of clinical isolates. Due to its low bioavailability, it is delivered by inhalation via the Diskhaler , 10 mg twice daily, or intranasally 2-4 times daily for 5 days. After an intravenous dose of 1 -16 mg, the median elimination half-life was ti/2 = 7 h, the volume of distribution at steady state was Vdss = 16 L, and 90% of the dose was excreted unchanged in the urine. After intranasal and inhaled (dry powder) administration, maximum serum concentrations occurred within 2h and the terminal phase half-lives were 3.4 and 2.9 h, respectively. The bioavailabilities were 10 and 25%, respectively, and 20% after inhalation of zanamivir (2) by nebulizer. 

Oseltamivir (1) is a prodrug of GS-4071 (7, Fig. 7.2). It is also a potent competitive inhibitor of viral neuraminidase glycoprotein for both influenza A and B types. Similar to zanamivir (2), oseltamivir (1) is also the fmit of SBDD in the sense that the protein structure directed the design of the ligand (sialic acid) and the protein-bound ligand conformation is close to the designed stmcture. In particular, the neuraminidase active site contains several 

Tamifiu and Relenza did not sell well at first for common fiu, because doctors and the public choose the fiu vaccine for prevention. Therefore, antivirals as treatment were not profitable, so much so that Roche scaled back their marketing efforts for Tamifiu. Gilead accused Roche of a consistent record of inactivity and neglect and wanted to take back its right in 2005. The issue was settled after Roche increased their compensation to Gilead. 

Interestingly, the third neuraminidase inhibitor, peramivir, saw an incarnation after the avian fiu scare. Peramivir was developed by BioCryst Pharmaceuticals and licensed to Johnson Johnson (Chand et al., 2005). However, because the bioavailability of peramivir was low and the prospective market small, Johnson Johnson pulled out of the alliance. In 2005, peramivir was regaining its life as a possible drug delivered intravenously. 

Shikimic acid is isolated from Chinese star anis, Illicium verum, and quinic acid is extracted from the bark of Cinchona trees. Although both compounds can be found in many other plants, their isolation and purification are cumbersome. A fermentation production process of shikimic acid from other renewables such as glucose seems to be successful [46]. 

However, the two syntheses of Tamiflu, involving two potentially hazardous azide-containing intermediates, need further improvements. A recently published short and enantioselective pathway starting from acrylic acid and 1,3-butadiene looks promising [47]. 

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Figure 4.18 The structure of Tamiflu (oseltamivir phosphate), an antiviral agent active against type A influenza, and a molecular model of its minimum-energy conformation, as calculated by molecular mechanics.

Table sugar, sec Sucrose Tagatose, structure of, 975 Talose. configuration of, 982 Tamiflu, molecular model of, 130 Tamoxifen, synthesis of, 744 Till] DNA polymerase, PCR and, 1117 Tartaric acid, stereoisomers of, 305-306... 

Shie J-J, Fang J-M, Wang S-Y, Tsai K-C, Cheng Y-SE, Yang A-S, Hsiao S-C, Su C-Y, Wong C-H (2007) Synthesis of Tamiflu and its phosphonate congeners possessing potent anti-influenza activity. J Am Chem Soc 129 11892-11893... 

Oseltamivir, better known as Tamiflu, is the antiviral worldwide employed for the treatment of influenza (flu). Due to the importance of that drug for treating regular seasonal flu and its potential use in the case of pandemic flu scenarios, it is... 

A highly useful and important regioselective reduction of substrate 84 leads to a mixture of 3-hydroxy ethers 85 and 86 in a 32 1 ratio (Eq. 306). Compound 85 is further converted to the anti-influenza drug oseltamivir phosphate, better known as Tamiflu .498... 

The neuramidase inhibitor oseltamivir phosphate was discovered by Gilead Sciences and developed by Roche Pharmaceuticals under the name of Tamiflu (Scheme 5.13) to be used as an orally active antiviral compound for prevention and treatment of influenza infections. Because of the recent emergence of the avian flu, the demand for Tamiflu has gained momentum. Two industrially feasible syntheses are known, starting from (—)-shikimic acid and (—)-quinic acid, respectively (Scheme 5.13) [45]. 

Exhibit 3.7 Development of Zanamivir (Relenza) and Oseltamivir (Tamiflu)... 

Two drugs were designed zanamivir (Relenza) by Glaxo Wellcome and oseltamivir (Tamiflu) by Roche. Zanamivir is a powder that has to be inhaled, and oseltamivir is an oral drug. 

Imatinib mesylate (Gleevec, Novartis), zanamivir (Relenza, GlaxoSmithKline), and oseltamivir (Tamiflu, Roche) are examples of drugs (Exhibits 3.11 and 3.7) that show the successful contributions of rational drug design. For example, the X-ray structure of angiotensin converting enzyme (ACE) has been reported (see Exhibit 11.2), and this may pave the way for more effective ACE inhibitors to be developed for the treatment of hypertension and heart disorders. 

Corey, E. J. Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586. Choung U. Kim now works at Gilead Sciences Inc., a company specialized in antiviral drugs in Foster City, CaUfomia, where he co-discovered oseltamivir (Tamiflu). 

Eliseev and coworkers subsequently reported a follow-up study on their DCC system using ketones in place of aldehydes and the same Tamiflu analog 13 as the scaffold [12]. 

Scheme 66 Iminium ion catalysed Diels-Alder reaction in the synthesis of tamiflu...

Oseltamivir (Tamiflu) Palivizumab (Synagis) Peg Interferon Alfa-2a (Pegsys)... 

Two ciT-dihydroxylation reactions of alkenes formed steps in the synthesis of the antiviral drug (-)-oseltamvir ( tamiflu ) were carried out with RuO /aq. Na(IO )/ EtOAc-CH3CN/4°C [169]. Terminal alkene groups in nucleosides were oxidised to alcohols by RuClj/aq. Na(lO )/EtOAc-CH3CN/0°C thus 3,5-di-0-benzyl-l,2-di-O-isopropylidene-3-C-vinyl-a-D-ribofuranose (1) gave the diol (2) which, on cleavage with Na(lO ) and reduction with NaBH yielded 3,5-di-0-benzyl-l,2-di-O-isopropylidene-3-C-hydroxy-methyl-a-D-ribofuranose (3) (Fig. 3.4) [170]. 

A step in the synthesis of the antiviral drug (-)-oseltamivir (Tamiflu) was the conversion of an amide to an imide with RuO /aq. NaCIO VCH Cl [74],... 

NEURAMINIDASE INHIBITORS FOR INFLUENZA OSELTAMIVIR PHOSPHATE (TAMIFLU ) AND ZANAMIVIR (RELENZA )... 

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