Ethyl ester prodrugs, hydrolysis

Pharmacology Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. 

Oseltamivir is an antiviral drug whose phosphate salt is marketed by Hoffmann-La Roche (Basel, Switzerland) under the trade name Tamiflu sold as capsules containing 30 mg, 45 mg, or 75 mg oseltamivir for oral use. It is indicated for the treatment of uncomplicated acute infection caused by influenza A or B virus in patients older than 1 year of age who have been symptomatic for no more than 2 days. Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. ... 

A comparison between carbamoylmethyl and aminoalkyl esters has been reported for a small series of prodrugs of ibuprofen (8.28) [39]. A further interest of this work is the systematic comparison made between the enantiomers of ibuprofen, i. e., the active (+)-(S)-form and the inactive (-)-(/ )-form. As shown in Table 8.4, the ethyl esters were hydrolyzed very slowly in human plasma, with t1/2 values in the order of 100 - 200 h. In contrast, the hydrolysis of the carbamoylmethyl and aminoalkyl esters occurred with t1/2 values in the order of some or several minutes. The carbamoylmethyl esters were hydrolyzed very rapidly with low substrate enantioselectivity, while the 2-(imidazol-l-yl)ethyl esters were hydrolyzed somewhat more slowly and with marked substrate enantioselectivity. 

Lipophilic prodrugs can also be derived from a carboxylic function, the most commonly used derivatives being carboxylic esters. Simple esters of aliphatic alcohols are attractive as they are cheap to prepare, chemically stable, and yield harmless hydrolysis products." Typical representatives of such prodrugs are tyrosine methyl ester," levodopa ethyl ester," nipecotic acid ethyl ester," enala-prilat ethyl ester," " " trandolapril," y-aminobutyric acid cetyl ester" " and methotrexate cetyl ester." ... 

Enalapril, (S)-l-[N-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl-L-proline, an orally active inhibitor of the angiotensinconverting enzyme (ACE). After oral administration, the prodrug enalapril (ICso = 1.2 X 10 M) is primarily bioactivated in the liver by hydrolysis of the ethyl ester to yield enalaprilat (IC50 =... 

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