Taocui Zhang , Lisha Lin , Lin Ren , Huifang Sun , Weili Wang , Shuang Liu , Shanni Li , Chuang Xiao , Na Gao , Jinhua Zhao
{"title":"抗凝血剂十四糖 oHG-14 作为一种内在十肽酶抑制剂的结构和药代动力学/药效学研究","authors":"Taocui Zhang , Lisha Lin , Lin Ren , Huifang Sun , Weili Wang , Shuang Liu , Shanni Li , Chuang Xiao , Na Gao , Jinhua Zhao","doi":"10.1016/j.thromres.2024.109041","DOIUrl":null,"url":null,"abstract":"<div><p>The intrinsic tenase complex (iXase) is an attractive antithrombotic target to treat or prevent pathological thrombosis with negligible bleeding risk. Fucosylated glycosaminoglycan (FG) is a promising anticoagulant by inhibiting iXase. A depolymerized FG (dHG-5) as an anticoagulant has been approved for clinical trials. Given that dHG-5 is a multi-component drug candidate consisting of a homologous series of oligosaccharides, it is difficult to predict a clear pharmacokinetics. Here, as a major oligosaccharide component, the tetradecasaccharide (oHG-14) was purified from dHG-5 and its structure was defined as L-Fuc<sub>3S4S</sub>-α(1,3)-L-Δ<sup>4,5</sup>GlcA-α(1,3)-{D-GalNAc<sub>4S6S</sub>-β(1,4)-[L-Fuc<sub>3S4S</sub>-α(1,]3)-D-GlcA-β(1,3)-}<sub>3</sub>-D-GalNAc<sub>4S6S</sub>-β(1,4)-[L-Fuc<sub>3S4S</sub>-α(1,]3)-D-GlcA-ol. oHG-14 showed potent iXase inhibitory activity <em>in vitro</em> and antithrombotic effect <em>in vivo</em> comparable to dHG-5. After single subcutaneous administration of oHG-14 at 8, 14.4 and 32.4 mg/kg to rats, the absolute bioavailability was 71.6 %–80.9 % determined by the validated bioanalytical methods. The maximum concentration (<em>C</em><sub><em>max</em></sub>) was 3.73, 8.07, and 11.95 μg/mL, respectively, and the time reaching <em>C</em><sub><em>max</em></sub> (<em>T</em><sub><em>max</em></sub>) was about 1 h. oHG-14 was mainly excreted by kidney as the parent compound with the elimination kinetics of first-order linear model. Anticoagulant activity of oHG-14 was positively correlated with its concentration in rat plasma. The pharmacokinetics/pharmacodynamics (PK/PD) of oHG-14 is similar to that of dHG-5. This study could provide supportive data for the clinical trial of dHG-5 and further development of pure oligosaccharide as an antithrombotic drug candidate.</p></div>","PeriodicalId":23064,"journal":{"name":"Thrombosis research","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor\",\"authors\":\"Taocui Zhang , Lisha Lin , Lin Ren , Huifang Sun , Weili Wang , Shuang Liu , Shanni Li , Chuang Xiao , Na Gao , Jinhua Zhao\",\"doi\":\"10.1016/j.thromres.2024.109041\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The intrinsic tenase complex (iXase) is an attractive antithrombotic target to treat or prevent pathological thrombosis with negligible bleeding risk. Fucosylated glycosaminoglycan (FG) is a promising anticoagulant by inhibiting iXase. A depolymerized FG (dHG-5) as an anticoagulant has been approved for clinical trials. Given that dHG-5 is a multi-component drug candidate consisting of a homologous series of oligosaccharides, it is difficult to predict a clear pharmacokinetics. Here, as a major oligosaccharide component, the tetradecasaccharide (oHG-14) was purified from dHG-5 and its structure was defined as L-Fuc<sub>3S4S</sub>-α(1,3)-L-Δ<sup>4,5</sup>GlcA-α(1,3)-{D-GalNAc<sub>4S6S</sub>-β(1,4)-[L-Fuc<sub>3S4S</sub>-α(1,]3)-D-GlcA-β(1,3)-}<sub>3</sub>-D-GalNAc<sub>4S6S</sub>-β(1,4)-[L-Fuc<sub>3S4S</sub>-α(1,]3)-D-GlcA-ol. oHG-14 showed potent iXase inhibitory activity <em>in vitro</em> and antithrombotic effect <em>in vivo</em> comparable to dHG-5. After single subcutaneous administration of oHG-14 at 8, 14.4 and 32.4 mg/kg to rats, the absolute bioavailability was 71.6 %–80.9 % determined by the validated bioanalytical methods. The maximum concentration (<em>C</em><sub><em>max</em></sub>) was 3.73, 8.07, and 11.95 μg/mL, respectively, and the time reaching <em>C</em><sub><em>max</em></sub> (<em>T</em><sub><em>max</em></sub>) was about 1 h. oHG-14 was mainly excreted by kidney as the parent compound with the elimination kinetics of first-order linear model. Anticoagulant activity of oHG-14 was positively correlated with its concentration in rat plasma. The pharmacokinetics/pharmacodynamics (PK/PD) of oHG-14 is similar to that of dHG-5. This study could provide supportive data for the clinical trial of dHG-5 and further development of pure oligosaccharide as an antithrombotic drug candidate.</p></div>\",\"PeriodicalId\":23064,\"journal\":{\"name\":\"Thrombosis research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2024-05-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Thrombosis research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0049384824001737\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Thrombosis research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0049384824001737","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor
The intrinsic tenase complex (iXase) is an attractive antithrombotic target to treat or prevent pathological thrombosis with negligible bleeding risk. Fucosylated glycosaminoglycan (FG) is a promising anticoagulant by inhibiting iXase. A depolymerized FG (dHG-5) as an anticoagulant has been approved for clinical trials. Given that dHG-5 is a multi-component drug candidate consisting of a homologous series of oligosaccharides, it is difficult to predict a clear pharmacokinetics. Here, as a major oligosaccharide component, the tetradecasaccharide (oHG-14) was purified from dHG-5 and its structure was defined as L-Fuc3S4S-α(1,3)-L-Δ4,5GlcA-α(1,3)-{D-GalNAc4S6S-β(1,4)-[L-Fuc3S4S-α(1,]3)-D-GlcA-β(1,3)-}3-D-GalNAc4S6S-β(1,4)-[L-Fuc3S4S-α(1,]3)-D-GlcA-ol. oHG-14 showed potent iXase inhibitory activity in vitro and antithrombotic effect in vivo comparable to dHG-5. After single subcutaneous administration of oHG-14 at 8, 14.4 and 32.4 mg/kg to rats, the absolute bioavailability was 71.6 %–80.9 % determined by the validated bioanalytical methods. The maximum concentration (Cmax) was 3.73, 8.07, and 11.95 μg/mL, respectively, and the time reaching Cmax (Tmax) was about 1 h. oHG-14 was mainly excreted by kidney as the parent compound with the elimination kinetics of first-order linear model. Anticoagulant activity of oHG-14 was positively correlated with its concentration in rat plasma. The pharmacokinetics/pharmacodynamics (PK/PD) of oHG-14 is similar to that of dHG-5. This study could provide supportive data for the clinical trial of dHG-5 and further development of pure oligosaccharide as an antithrombotic drug candidate.
期刊介绍:
Thrombosis Research is an international journal dedicated to the swift dissemination of new information on thrombosis, hemostasis, and vascular biology, aimed at advancing both science and clinical care. The journal publishes peer-reviewed original research, reviews, editorials, opinions, and critiques, covering both basic and clinical studies. Priority is given to research that promises novel approaches in the diagnosis, therapy, prognosis, and prevention of thrombotic and hemorrhagic diseases.