title: Synthesis and biopharmaceutical studies of JLTN as potential dasatinib prodrug.
abstract: Dasatinib was identified as a potent orally administered Src/Abl kinase inhibitor with excellent antiproliferative activity against Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. The low bioavailability of Dasatinib may be due to both incomplete oral absorption and first-pass metabolism. A prodrug, JLTN, was synthesized to minimize the first-pass effect of Dasatinib and improve the oral bioavailability following oral administration via targeting intestinal peptide transporter and enhancing chemical stability. Biological evaluation data indicated that there was a 150%-fold increase in oral bioavailability of this prodrug compared to the parent drug Dasatinib in monkeys.
authors.affiliation: Department of Nuclear Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Lang
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Lu
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Wang
authors.forename: Shih-Chen
authors.initials: SC
authors.lastname: Wang
mesh_terms: D000818:Animals; D000069439:Dasatinib; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D008253:Macaca mulatta; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics*
chemical_list: C586419:N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1,3-thiazole-5-carboxamide; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib