title: Synthesis of the alkylated active metabolite of tipidogrel.
abstract: Tipidogrel (3), an effective anti-platelet drug candidate working by irreversibly inhibiting P2Y12 receptor, holds great promise in overcoming clopidogrel resistance and increasing bioavailability. As a prodrug like other thienopyridines, it metabolizes through thiophene ring opening to form active metabolites 3a and 3b, nevertheless they are easily to form disulfide bond. Derivatization of 3a and 3b via alkylation with MPBr can prevent disulfide conjugation and ensure reliable pharmacokinetic results. Thus, in order to support its pre-clinical studies on efficiencies in the formation of tipidogrel active metabolites, 13a and 13b were synthesized via seven steps of chemosynthesis and incubation with MPBr in rat plasma in vitro. The resulting crude productions were purified by semi-preparative HPLC to give Z configuration 13a and E configuration 13b. In LC-MS/MS spectra, they showed identical fragmentation pattern and retention time with M-13a and M-13b, the MPBr-derivatives of active metabolites of tipidogrel in rats. Thus, 13a and 13b were the anticipated alkylated active metabolite of tipidogrel. In addition, in the nucleophilic substitution of thioacetate with compound 11, besides the anticipated compounds 12a and 12b, their isomers compounds 12c and 12d were detected, whose structures were confirmed and the corresponding mechanism was presented.
authors: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors: Shuang
authors: S
authors: Zhi
authors: Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors: Guangping
authors: G
authors: Xia
authors: Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors: Ying
authors: Y
authors: Liu
authors: Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin 300020, China.
authors: Zunwei
authors: Z
authors: Tao
authors: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors: Ligong
authors: L
authors: Chen
authors: Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. Electronic address: liudk@tjipr.com.
authors: Dengke
authors: D
authors: Liu
mesh_terms: D000478:Alkylation; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D000077144:Clopidogrel; D006207:Half-Life; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D058921:Purinergic P2Y Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D058925:Receptors, Purinergic P2Y12 / Q000737:chemistry / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
chemical_list: D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D011725:Pyridines; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; C446540:thienopyridine; C000603605:tipidogrel; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: Active metabolite; Bioavailability; Clopidogrel resistance; Derivatization; P2Y(12) receptor inhibitor; Tipidogrel