Oseltamivir

Oseltamivir phosphate (Tamiflu ) was developed for the treatment and prevention of influenza virus infections. The key starting material of one commercial route is 

Sample preparation Condition a 100 mg C18 SPE cartridge (Varian) with 1 mL MeCN water 75 25 and 1 mL 10 mM HCl in MeCNiwater 5 95. Mix 100 [xL plasma with 25 pL 1 M citric acid and 100 pL 1 pg/mL IS in 50 mM sodium dihydrogen phosphate, add to the SPE cartridge, wash with 1 mL 10 mM HCl in MeCN water 5 95, elute with 400 pL MeCN water 75 25, add 50 pL 20 mM KCN in 200 mM pH 6.5 phosphate buffer to the eluate, add 50 pL 20 mM naphthalene-2,3-dialdehyde in MeCN, vortex, heat at 40° for 45 min. Evaporate to dryness under reduced pressure at room temperature, reconstitute the residue with 100 pL 50 mM sodium dihydrogen phosphate, centrifuge, inject a 40 pL aliquot. 

Mobile phase MeCN water 27 73 containing 50 mM sodium acetate Flow rate 2 Injection volume 40 Detector F ex 420 em 472 

Retention time 5.2 (for GS4071 the free acid active metabolite) 

Internal standard GS4057 ((3R, 4R, 5iS)-4-acetainido- 5 -ainino-3-(l-cyclopentanoxy)-1-cyclohexene-l-carboxylic acid) (4.3) 

Eisenberg, E.J. Gundy, K.C. High-performance liquid chromatographic determination of GS4071, a potent inhibitor of influenza neuraminidase, in plasma by precolumn fluorescence derivatization with naphthalenedialdehyde, J.Chromatogr.B, 1998, 716, 267-273. 

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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.

The influenza virus inhibitors, zanamivir, and oseltamivir, act outside the cell after virus particles have been formed. The dtugs have been designed to fit into the active site of the viral envelope enzyme neuraminidase, which is required to cleave sialic acid off the surface of the producing cells. When its activity is blocked, new virus particles stay attached to the cell surface through binding of the virus protein hemagglutinin to sialic acid and are prevented from spreading to other cells. 

Neuraminidase inhibitors are the major class of drugs to treat or to prevent the infection with influenza viruses. Currently, two neuraminidase inhibitors are available, zanamivir and oseltamivir, which block the release of new influenza vims from infected host cells and thereby stop the spread of infection. The enzyme neuraminidase is a surface glycoprotein present on all influenza viruses. There are nine influenza neuraminidase sub-types known of which subtypes N1 and N2 appear to be the most important ones. Neuraminidase inhibitors are effective against all neuraminidase subtypes. The activity of the neuraminidase is required for the newly... 

C5H12O2 77-76-9) see Atorvastatin calcium Dibekacin Docetaxel Doxifluridine Epirubicin Indinavir sulfate lotrolan Misoprostol Oseltamivir acetonitrile... 

C5H10O 96-22-0) see Molindone Oseltamivir A jA -diethylleucine ethyi ester C12H25NO2) see Lencinocaine A, /V-diethyileucine 4-nitrophenyl ester (CnH2(,Ni04) see Leucinocaine diethyl malonate... 

C jHijO 77-95-2) see Oseltamivir quinic acid y-lactone (C7H,oO, 27783-00-2) see Cynarine quinine... 

Benazepril Docetaxel Fluazacort Imiquimod Irbesartan Midodtine Oseltamivir Paclitaxel Pemirolast Pranlukast Tazanolast Tranylcypromine Zanamivir Zidovudine sodium benzenesultinate... 

C2H5NaO 141-52-6) see Azelastine Einorfazone Methyprylon Oseltamivir Pentobarbital Promestriene Propallylonal Protionamide sodium 2-ethylhexanoate... 

CHF3O3S 1493-13-6) see Loratadine Oseltamivir trifluoromethanesulfonic acid 4-[(2-methylpropyl)amino]-... 

Despite the presence of the more lipophilic side-chain in 18, compared to the glycerol side-chain of 12, a pro-drug strategy was necessary to achieve sufficient oral bioavailabUity. Thus, the ethyl ester pro-drug form of 18, oseltamivir (GS 4104,... 

Fig. 6 Superimposition of inhibitors and key active site residues from crystal structures of oseltamivir carboxylate 18 brown carbons, PDB - 2qwk) and Neu5Ac2en 4 (green carbons, PDB - IfSb) in complex with influenza A virus siaMdase. Note the alternative conformations of the...

Fig. 7 The influenza virus A sialidase active site showing the five potential inhibitor binding subsites (with S5 containing the hydrophobic pocket formed by reorientation of the Glu276 side-chain), with oseltamivir carboxylate 18 placed in the active site...

Further SAR studies on the cyclopentane scaffold have included variation of the hydrophobic side-chain to incorporate a carboxamide substituent (Chand et al. 2004), equivalent to the C6-carboxamide derivatives of zanamivir, and extension of the length of the hydrophobic side-chains (Chand et al. 2005a). Analogues that incorporate a longer 4-heptyl side-chain showed comparable efficacy to 34 upon oral and intranasal administration in mice, and comparable or better efficacy than oseltamivir and zanamivir (Chand et al. 2005a). 

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