title: Synthesis and in Vitro and in Vivo Anticoagulant and Antiplatelet Activities of Amidino- and Non-Amidinobenzamides.
abstract: Three amidino- and ten non-amidinobenzamides were synthesized as 3-aminobenzoic acid scaffold-based anticoagulant and antiplatelet compounds. The anticoagulant activities of thirteen synthesized compounds 1-13, and 2b and 3b as prodrugs were preliminary evaluated by screening the prolongation of activated partial thromboplastin time (aPTT) and prothrombin time (PT) in vitro. From the aPTT results obtained, two amidinobenzamides, N-(3'-amidinophenyl)-3-(thiophen-2''-ylcarbonylamino) benzamide (1, 33.2 ± 0.7 s) and N-(4'-amidinophenyl)-3-(thiophen-2''-ylcarbonylamino) benzamide (2, 43.5 ± 0.6 s) were selected to investigate the further anticoagulant and antiplatelet activities. The aPTT results of 1 (33.2 ± 0.7 s) and 2 (43.5 ± 0.6 s) were compared with heparin (62.5 ± 0.8 s) in vitro at 30 μM. We investigated the effect of 1 and 2 on blood anticoagulant activity (ex vivo) and on tail bleeding time (in vivo) on mice. A tail cutting/bleeding time assay revealed that both 1 and 2 prolonged bleeding time in mice at a dose of 24.1 g/mouse and above. Compounds 1 and 2 dose-dependently inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. In addition, 1 and 2 were evaluated on the inhibitory activities of thrombin and FXa as well as the generation of thrombin and FXa in human umbilical vein endothelial cells (HUVECs). Collectively, 1 and 2 possess some antiplatelet and anticoagulant activities and offer a basis for development of a novel antithrombotic product.
authors.affiliation: College of Pharmacy, Catholic University of Daegu, Hayang-ro 13-13, Hayang-eup, Gyeongsan-si, Gyeongbuk 712-702, Korea. soohyun0320@cu.ac.kr.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea. ByWonhwalee@gmail.com.|Department of Biochemistry and Cell Biology, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 700-422, Korea. ByWonhwalee@gmail.com.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Lee
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea. baejs@knu.ac.kr.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Catholic University of Daegu, Hayang-ro 13-13, Hayang-eup, Gyeongsan-si, Gyeongbuk 712-702, Korea. masook@cu.ac.kr.
authors.forename: Eunsook
authors.initials: E
authors.lastname: Ma
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D001549:Benzamides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D001777:Blood Coagulation / Q000187:drug effects; D015951:Factor Xa / Q000378:metabolism; D006470:Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D011517:Prothrombin Time; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000925:Anticoagulants; D001549:Benzamides; D010975:Platelet Aggregation Inhibitors; D013917:Thrombin; D015951:Factor Xa
keywords: aPTT; amidinobenzamide; anticoagulant; antiplatelet; nonamidinobenzamide