, Volume 18, Issue 4, pp 1523-1540
Date: 23 Jul 2011

Computer-assisted design for atenolol prodrugs for the use in aqueous formulations

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Abstract

Based on stability studies on the drugs atenolol and propranolol and some of their derivatives it is believed that increasing the lipophilicity of the drug will lead to an increase in the stability of its aqueous solutions and will provide a prodrug system with the potential for releasing atenolol in a controlled manner. Using DFT theoretical calculations we have calculated an intramolecular acid catalyzed hydrolysis in nine maleamic (4-amino-4-oxo-2butenoic) acids (Kirby’s N-alkylmaleamic acids), 19. The DFT calculations confirmed that the acid-catalyzed hydrolysis mechanism in these systems involves: (1) a proton transfer from the hydroxyl of the carboxyl group to the adjacent amide carbonyl carbon, (2) an approach of the carboxylate anion toward the protonated amide carbonyl carbon to form a tetrahedral intermediate; and (3) a collapse of the tetrahedral intermediate into products. Furthermore, DFT calculations in different media revealed that the reaction rate-limiting step depends on the reaction medium. In aqueous medium the rate-limiting step is the collapse of the tetrahedral intermediate whereas in the gas phase the formation of the tetrahedral intermediate is the rate-limiting step. Furthermore, the calculations establish that the acid-catalyzed hydrolysis efficiency is largely sensitive to the pattern of substitution on the carbon-carbon double bond. Based on the experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values for processes 19 we have calculated the t1/2 values for the conversion of the two prodrugs to the parental drug, atenolol. The calculated t1/2 values for ProD 1–2 are predicted to be 65.3 hours and 11.8 minutes, respectively. Thus, the rate by which atenolol prodrug undergoes cleavage to release atenolol can be determined according to the nature of the linker of the prodrug (Kirby’s N-alkylmaleamic acids 1–9).

Figure

Conversion of aqueous-stable atenolol prodrug to atenolol via intramolecular hydrolysis process