title: Synthesis and thrombolytic activity of new thienopyrimidinone derivatives.
abstract: It has been observed that ticlopidine and clopidogrel show, apart from their delayed antiplatelet properties, an immediate and transient thrombolytic action related to the ability of these thienopyridines to stimulate the secretory function of vascular endothelium. With the objective to construct new molecules with identical thrombolytic potency but at a higher level, we carried out different structural modifications in the thienopyridine chemical molecule to conclude that the presence of a second N atom in the pyridine cycle (yielding pyrimidine moiety) and the presence of an additional cycle fused to the thienyl ring would lead to enhanced thrombolytic effects. Here we report the six-step synthesis of a series of new benzothienopyrimidinone derivatives characterized by this searched for potent thrombolytic activity. The pharmacological assay used anaesthetised Wistar rats with extracorporal circulation in which arterial blood superfused thrombi adhering to a strip of collagen. Weight of thrombi was continuously monitored. Six compounds of the series were much more potent thrombolytic agents than their thienopyridine references: the effective thrombolytic dose that produced 30% of maximum thrombolysis (ED30) was at a range of 8 to 170 microg kg(-1) as compared with ED30 values of 16000 to 20000 microg kg(-1) for clopidogrel and ticlopidine respectively. Especially with the most active compound, this difference in the threshold thrombolytic dose, giving an intensity of action higher by three orders of magnitude, was accompanied by a lengthening of the response. Apart from that these compounds have shown to be synthetic thrombolytics, they certainly deserve further studying.
authors.affiliation: Chair of Pharmacology, Medical College of Jagiellonian University, Cracow, Poland.
authors.forename: J P
authors.initials: JP
authors.lastname: Dupin
authors.forename: R J
authors.initials: RJ
authors.lastname: Gryglewski
authors.forename: D
authors.initials: D
authors.lastname: Gravier
authors.forename: G
authors.initials: G
authors.lastname: Hou
authors.forename: F
authors.initials: F
authors.lastname: Casadebaig
authors.forename: J
authors.initials: J
authors.lastname: Swies
authors.forename: S
authors.initials: S
authors.lastname: Chlopicki
mesh_terms: D000818:Animals; D001158:Arteries; D000077144:Clopidogrel; D005112:Extracorporeal Circulation; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013927:Thrombosis / Q000503:physiopathology; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D005343:Fibrinolytic Agents; D011728:Pyridones; D000077144:Clopidogrel; D013988:Ticlopidine