Design, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditions
Design, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditions
Date
2013-07-13
Authors
Karaman, Rafik
Ghareeb, Hiba
Dajani, Khuloud Kamal
Hallak, Hussein
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Science+Business Media Dordrecht
Abstract
Based on density functional theory (DFT) calculations
for the acid-catalyzed hydrolysis of several
maleamic acid amide derivatives four tranexamic acid
prodrugs were designed. The DFT results on the acid catalyzed
hydrolysis revealed that the reaction rate-limiting
step is determined on the nature of the amine leaving
group. When the amine leaving group was a primary amine
or tranexamic acid moiety, the tetrahedral intermediate
collapse was the rate-limiting step, whereas in the cases by
which the amine leaving group was aciclovir or cefuroxime
the rate-limiting step was the tetrahedral intermediate formation.
The linear correlation between the calculated DFT
and experimental rates for N-methylmaleamic acids 1–7
provided a credible basis for designing tranexamic acid
prodrugs that have the potential to release the parent drug
in a sustained release fashion. For example, based on the
calculated B3LYP/6-31G(d,p) rates the predicted t1/2 (a
time needed for 50 % of the prodrug to be converted into
drug) values for tranexamic acid prodrugs ProD 1–ProD 4
at pH 2 were 556 h [50.5 h as calculated by B3LYP/
311?G(d,p)] and 6.2 h as calculated by GGA: MPW1K),
253 h, 70 s and 1.7 h, respectively. Kinetic study on the
interconversion of the newly synthesized tranexamic acid
prodrug ProD 1 revealed that the t1/2 for its conversion to
the parent drug was largely affected by the pH of the
medium. The experimental t1/2 values in 1 N HCl, buffer
pH 2 and buffer pH 5 were 54 min, 23.9 and 270 h,
respectively.
Description
Keywords
Tranexamic acid, Prodrugs, Menstrual, bleeding, Fibrinolysis, Proton transfer, Traumatic, haemorrhage, Hemophilia