新型ET_A受体选择性拮抗剂ETP-508衍生物抗肺动脉高压作用的药效学及毒性的筛选研究

目的该文对军事医学科学院毒物药物研究所合成的新型内皮素A(ETA)受体选择性拮抗剂ETP-508衍生物进行抗肺动脉高压的药效学及毒性的筛选研究,期望获得高效低毒的候选化合物。方法采用内皮素-1(ET-1)诱发离体大鼠主动脉环收缩、整体大鼠颈动脉压升高实验模型进行生物活性筛选;对活性较好的化合物进一步在慢性缺氧诱发大鼠肺动脉高压实验模型进行抗肺动脉高压的药效学评价;采用小鼠急性毒性试验及大鼠注射部位刺激性试验初步评价化合物的毒性。结果部分化合物(GF004、GF009、GF012、GF022、GF052、GF063、GF084)能有效抑制ET-1(10nmol·L-1)诱发的离体大鼠主动脉环收缩,其IC50值在10～100nmol·L-1水平;在整体水平上述化合物(2mg·kg-1,sc)抑制ET-1(3.7μg·kg-1)诱发的大鼠颈动脉压升高效应(P<0.05),抑制率为25%～45%,其中GF009和GF063抑制效应与ETP-508相当;在病理模型上,化合物GF009(25、50mg·kg-1,sc)和GF063(20、40mg·kg-1,sc)降低慢性缺氧诱发的大鼠肺动脉高压(P<0.05),抑制率分别为45.3%,59.9%和61.3%,73.7%,其效应与ETP-508相当。此外,GF009和GF063致小鼠急性毒性LD50值比ETP-508明显增加,皮下给药致大鼠注射部位刺激性明显减轻。结论以上结果提示,通过筛选获得的新型选择性ETA受体拮抗剂GF009和GF063不仅能有效地抑制慢性缺氧诱发的大鼠肺动脉高压,效果与ETP-508相当,而且毒性比ETP-508明显降低,值得进一步深入研究。

Pharmacological and toxicological screening of chemically-new ETA receptor antagonists,derivates of ETP-508,on pulmonary hypertension in vivo and in vitro

Aim To synthesizeGF-Series of compounds,derivatives of compound ETP-508,and to evaluate the biological activity and primary toxicity of compounds of GF-Series to obtain some active compounds with low toxicity.Method The biological activity of these compounds was screened in isolated rat aortic ring experiment and in systemic arterial pressure of anesthetized rat experiment.Among these derivates,some active compounds were selected for further pharmacological characterization on rat pulmonary hypertension induced by hypoxia.Meanwhile,the primary toxicity of compounds was investigated in mouse acute toxicity test and in rat injection site irritation test.Results In vitro,contraction induced by ET-1(10 nmol·L-1)in isolated rat aortic ring trial was inhibited by new compounds of GF004,GF009,GF012,GF022,GF052,GF063 and GF084,and the values of IC50 were in the range of 10～100 nmol·L-1.In vivo,the increase in systemic arterial pressure induced by ET-1(3.7 μg·kg-1)was significantly inhibited by 2 mg·kg-1(sc) compounds by intravenous infusion(P<0.05),and the inhibition ratio of which was in the range of 25%~45%.Furthermore,pretreatment with compound GF009(25 mg·kg-1,50 mg·kg-1,sc)or GF063(20 mg·kg-1,40 mg·kg-1,sc) could partly prevent chronic hypoxia-induced pulmonary hypertension(P<0.05)in rats,and the inhibition ratio of which was 45.3%,59.9% and 61.3%,73.7% respectively.The above pharmacological effects of GF009 and GF063 in vitro and in vivo were similar to those of ETP-508.Acute toxicity of new compounds in mice and the injection site irritation in rats were obviously lower compared with ETP-508.Conclusion GF009 and GF063 exhibit similar pharmacological effects on pulmonary hypertension and lower toxicity in vitro and in vivo compared with ETP-508,which was worth further investigation.