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