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- Title
Design, Synthesis, and Antisickling Investigation of a Thiazolidine Prodrug of TD-7 That Prolongs the Duration of Action of Antisickling Aromatic Aldehyde.
- Authors
Alhashimi, Rana T.; Ahmed, Tarek A.; Alghanem, Lamya; Pagare, Piyusha P.; Huang, Boshi; Ghatge, Mohini S.; Omar, Abdelsattar M.; Abdulmalik, Osheiza; Zhang, Yan; Safo, Martin K.
- Abstract
The synthetic allosteric effector of hemoglobin, TD-7 has been investigated as a potential therapeutic agent for the treatment of sickle cell disease. The pharmacologic activity of TD-7 is due to formation of a Schiff-base interaction between its aldehyde group and the two N-terminal αVal1 amines of hemoglobin, effectively inhibiting sickling of red blood cells. However, TD-7 faces a challenge in terms of poor oral bioavailability due to rapid in-vivo oxidative metabolism of its aldehyde functional group. To address this shortcoming, researches have explored the use of a L-cysteine ethyl ester group to cap the aldehyde group to form a thiazolidine aromatic aldehyde prodrug complex, resulting in the improvement of the metabolic stability of this class of compounds. This report details the synthesis of a thiazolidine prodrug of TD-7, referred to as Pro-7, along with a comprehensive investigation of Pro-7 functional and biological properties. In an in-vitro Hb modification and Hb oxygen affinity studies using normal whole blood, as well as erythrocyte sickling inhibition using sickle whole blood, Pro-7 exhibited a gradual onset but progressive increase in all activities. Additionally, in-vivo pharmacokinetic studies conducted with Sprague Dawley rats demonstrated that Pro-7 can undergo hydrolysis to release TD-7. However, the blood concentration of TD-7 did not reach the desired therapeutic level. These findings suggest that the incorporation of the L-cysteine ethyl ester group to TD-7 represents a promising strategy to enhance the metabolic stability of aromatic aldehydes that could lead to the development of a more effective drug for the treatment of sickle cell disease.
- Subjects
AROMATIC aldehydes; ETHYL esters; ERYTHROCYTES; SICKLE cell anemia; SPRAGUE Dawley rats; FORMYLATION; ETHYL group; IN vivo studies
- Publication
Pharmaceutics, 2023, Vol 15, Issue 11, p2547
- ISSN
1999-4923
- Publication type
Article
- DOI
10.3390/pharmaceutics15112547