Prodrugs proline

A. Bielawska, K. Bielawski, K. Chrzanowski, S. Wolczynski, Prolinase-Activated Prodrug for Cancer Chemotherapy. Cytotoxic Activity of Proline Analogue of Chlorambucil in Breast Cancer MCF-7 Cells , Farmaco 2000, 55, 736-741. 

Chrzanowski, K., Bielawska, A., and Palka, J. Proline analogue of melphalan as prodrug susceptible to the action of prolidase in breast cancer MDA-MB 231 cells. 11 Farmaco 58 1113-1119, 2003. 

To improve the oral properties of enalaprilat, Patchett and colleagues turned to a prodrug approach. Esters were made of only one and of both carboxyls, and fortunately only esters of the N-carboxyalkyl group were needed for good oral absorption. When the proline carboxyl is esterified, the resultant inhibitor would have been difficult to formulate, since closure to a diketopiperazine easily takes place. Although various esters were tried, none were clearly superior to the ethyl ester 20 (Table IV). 

Fosinopril Sodium. Fosinopril sodium. (4,S)-4-cyclo-hexyl-1 -I I l(/fS)-1 -hydroxy-2-methylpropoxy (4-phenyl-bu-(yl)phosphinyl acetyl -(.-proline sexlium salt (Monopril). is a phosphorus-containing ACE inhibitor. It is inactive but. serves us a prodrug. being completely hydrolyzed by intestinal and liver en/ymes to (he active diacid fosinoprilat. 

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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