Abstract
Patients who suffer from secondary iron overload, such as β-thalassemia, are heavily iron overloaded due to their dependence on frequent blood transfusions. Iron chelation therapy has been required for the treatment of the iron overload when the body iron homeostasis has been disrupted. CP20/deferiprone, which belongs to the 3-Hydroxypyridin-4-one (3-HPO) family, has been used as a clinically useful iron chelator by virtue of its oral activity and good iron mobilisation potency. However, it has been associated with some side effects due to the large dose administered, which is related to the extensive Phase II glucuronic acid conjugation at one of the essential iron chelation sites (3-hydroxyl group) in the liver. So novel iron chelators with reduced glucuronide conjugates at the 3-hydroxyl group are sought.The research questions approached in the thesis are to investigate the in vitro hepatic drug metabolism and in vivo iron mobilisation efficacy of 2nd generation 3-hydroxypyridin-4-one chelators. The specific aim is to screen their in vitro liver metabolic clearance profiles using liver microsomes and to select the candidate compounds with potential potency in iron chelation for further in vivo iron mobilisation efficacy study using a Fe59-Ferritin loaded rat model.
A rapid, but sensitive and selective bio-analytical method for screening and quantification of the hepatic in vitro metabolic clearance of novel 3-hydroxypyridin-4-ones has been developed. This new approach is suitable for screening a series of 3-HPOs with high-throughput. A series of 3- HPO derivatives including two stereoisomers of chiral compounds, deferiprone analogues and pegylated 3-HPOs have been screened using the developed method and have represented different structure related metabolic profiles, which are of great relevance to investigate the structure activity relationships. One of the chiral enantiomers, CN128, was demonstrated to be much less susceptible towards the glucuronidation conjugation enzyme in the in vitro microsomal model (the percentage of glucuronidation is only 20% less compared to that of CP20/deferiprone). Another HPO, the acetamido-alkyl analogue of deferiprone, CM1, was found to be extensively conjugated by glucuronic acid (the percentage of glucuronidation is roughly 70% less compared to that of CP20/deferiprone). However, CM1 possesses a higher LogP value compared with CP20/ deferiprone, consequently, it was predicted to remove intracellular iron more efficiently from iron overloaded sites. These two compounds were selected for the in vivo iron mobilisation efficacy study in a Fe59-Ferritin loaded rat model. CN128 displayed significantly higher iron mobilisation from the rat liver at lower doses when compared with therapeutic doses of CP20/deferiprone. CM1, although more effective than CP20/ deferiprone, was much less effective than CN128.
| Date of Award | 2016 |
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| Original language | English |
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| Supervisor | Robert Hider (Supervisor) & Peter Hylands (Supervisor) |