Ten new dabigatran derivatives (7a–j) with high docking scoring were designed, synthesised and biologically evaluated. The inhibitory in vitro activity of these compounds on thrombin was evaluated on the basis of preliminary activity screening results. The IC₅₀ values of compounds 7a, 7d and 7j were 1.92, 2.17 and 1.54 nM, respectively, and are equivalent to the dabigatran (IC₅₀ = 1.20 nM). Therefore, the most active compound, 7j, was selected to further investigate the anticoagulant activity in rats. Compound 7j presented excellent in vivo inhibitory effects on arteriovenous thrombosis, and the inhibition rate was (84.19 ± 1.14) %. The anticoagulant activity of compound 7k synthesised in the previous work was evaluated in vivo, and its inhibition rate was (85.58 ± 2.89) %. This rate was nearly equivalent to that of dabigatran (85.07 ± 0.61) %. Results indicated that compounds 7a, 7d, 7j and 7k can be further studied as novel antithrombin drug candidates.

设计，合成和生物评价了十个对接得分高的新达比加群衍生物（7a–j）。根据初步活性筛选结果评估了这些化合物对凝血酶的体外抑制活性。化合物7a，7d和7j的IC ₅₀值分别为1.92、2.17和1.54 nM，相当于达比加群（IC ₅₀ = 1.20 nM）。因此，选择了活性最高的化合物7j来进一步研究大鼠的抗凝活性。化合物7j对动静脉血栓形成具有优异的体内抑制作用，抑制率为（84.19±1.14）％。在体内评估了先前工作中合成的化合物7k的抗凝血活性，其抑制率为（85.58±2.89）％。该比率几乎等于达比加群（85.07±0.61）％。结果表明，化合物7a，7d，7j和7k可作为新型抗凝血酶候选药物进行进一步研究。