Preclinical Study on a Novel Fluoroderivative of Dabigatran Etexilate in Animal Models

Author:

Ren Yujie1,Li Chunlei2,Zhang Yujia1

Affiliation:

1. Green and Intelligent Pharmaceutical College, Zhejiang Guangsha Vocational and Technical University of Construction, Dongyang, Zhejiang Province, China; and

2. Department of Pharmaceutical Engineering, Shanghai Pharmaceutical School, Shanghai, China.

Abstract

Abstract: Here, the fluorinated derivative, R1, was synthesized from the fluorinated dabigatran derivative (R0). The in vivo pharmacokinetic characteristics of orally administered R1, R0 injection, and dabigatran etexilate in rats were compared. Safety evaluation results showed no significant changes in the QRS wave or PR and QT intervals in rat lead II electrocardiograms. The possible toxicity of R1 was studied using the limit test method, and no obvious toxicity occurred in mice after the acute oral administration of R1. R1 inhibited thrombin-induced platelet aggregation in a dose-dependent manner, had an inhibitory effect on platelet aggregation induced by arachidonic acid and adenosine diphosphate, could significantly prolong prothrombin time and activated partial thromboplastin time, and increased fibrinogen levels. R1 is the optimal candidate compound from among more than 100 candidate compounds designed and synthesized by our research group. It was first selected through preliminary in vitro anticoagulant activity screening and further through in vivo mouse activity testing. A systematic pharmacodynamic study showed that R1 was superior to the raw material drug dabigatran ester; particularly, the absolute bioavailability of R1 increased by 206%, and this can overcome the low bioavailability defect associated with the marketed drug dabigatran ester. Another safety assessment of R1 indicated that there were no risks of acute poisoning in rats and cardiac toxicity in mice or rats. Therefore, R1 can be considered a new candidate anticoagulant compound with great potential and significance for further clinical research.

Funder

Zhejiang Guangsha Construction Vocational Technology College for Research Startup Funding

Local Capacity Building Project of the Shanghai Municipal Science and Technology Commission

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Pharmacology

Reference18 articles.

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