Design,Synthesis And Bioactivity Evaluation Of Chiral 3-Hydroxypyridin-4-one Iron Chelators

Thalassemia is an infrequently seen geneitic disease. It is majorly classified intoα-thalassemia and P-thalassemia, of whichβ-thalassemia is more devastating due to its larger morbidity and fatality. The cause ofβ-thalassemia is mutation or loss ofβ-globin gene, so that biological synthesis ofβ-globin is largely reduced or completely stoped. Thus the heamoglobin level of patients is reduced, and erythronoclastic anemia is the other symptom ofβ-thalassemia. In China, morbidity of P-thalassemia is high in Guangxi, Guangdong, Hainan, Yunnan provinces, imposing a threat to the population in this area.Currently, the main stream treatment ofβ-thalassemia heavy is blood translation assisted with iron chelation therapy. In order to maintain a certain level of blood red cell, the patients has to undergo regular translational therapy. However, human body does not have an effective iron clearance mechanism. Excessive iron due to blood transfusion is accumulated in the body, particularly important organs such as heart, liver and spleen etc. Because of the redox reactions catalysed by excess iron (Ⅲ) ion, the tissues and organs are badly injured, threatening the life of patients. If they take no therapy or take translational therapy only, the mortality rate is very high in these P-thalassemia patients before they grow-up. Presently, there are only three commercially available iron chelators, Desferioxamine, Deferiprone and Deferasirox, all orphan drugs. The cost of thalassemia treatment is very high in China, a patient has to spend 14000 RMB for translational treatment and 16000 RMB for iron chelation therapy, and both of them have to be taken for life time. Currently, our country does not have iron chelating drugs that have our own intellectual property right. Therefore iron chelators are completely import dependent, and prices are very high.According to the current situation of treatment of thelassemia and iron overload, we designed and synthesized a series of chiral 3-hydroxypyridin-4-ones as iron chelators. Chemical structure and purity were determined by 1HNMR, polarimeter and HPLC methods, respectively. We have discovered that (R)-3-hydroxy-1-(1-hydroxy-3-phenylpropan-2-yl)-2-methylpyridin-4(1H)-one (Code CN128) has a lot of advantages compared to first-line clinical oral iron chelator Deferiprone (Code CP20). The advances are:1) high iron clearance efficiency, CN128 is three times more effective than Deferiprone to iron-overload rat model.2) CN128 has very high bioavailability, research in liver microsomal metabolism show that CN128 has very low glucuronidation inactivation rate in phaseⅠand phaseⅡliver microsomal metabolism test; and pharmacokinetics research show that bioavailability of CN128 is 95.2%.3) CN128 has low toxicity, research in mice acute toxicity show that LD50 of CN128 is 2.19 g/kg, twice as that of Deferiprone to mice; research in Beagle dog chronic toxicity show that CN128 was orally administered to Beagle dogs at 0.25 g/kg/day for a month, the dogs did not show apparent toxic reactions. Above all, CN128 has very good potential to become an iron chelating drug for clinical usage.