心血管类-降压药物资料文档.ppt

加框者为经临床试验证实为有益的药物，实线相连为最合理的组合 ESC/ESH抗高血压药物的联合治疗 推荐的降压联合治疗方案 利尿剂+β阻滞剂 利尿剂+ACE抑制剂或ARB CCB+ β阻滞剂 CCB +ACE抑制剂或ARB CCB +利尿剂 α阻滞剂+ β阻滞剂 化合物与AT1受体结合结合图（用SYBYL软件及有关数据库构建） 本课题组工作 课题组合成的新化合物与依贝沙坦优势构象拟合图（用Spartan软件） 化合物33剂量为15 mg/kg对SHR的MBP的影响 * * * * * * Substitute on the head region of Losartan Five-membered ring series IC50=3nM IC50=0.44nM IC50=1.3nM F=60%-80% Substitute on the head region of Losartan Five-membered ring series IC50=4nM Substitute on the head region of Losartan Six-membered ring series Substitute on the head region of Losartan Fusedheterocycle series IC50=110nM IC50=66nM Substitute on the head region of Losartan Fusedheterocycle series IC50=110nM PA2=7.89 F=80% Substitute on the head region of Losartan Fusedheterocycle series IC50=5.2nM PA2=8.4 Substitute on the head region of Losartan Linear chain amino acid series Chemical modifications on biphenyl region Biphenyl connected to a heteroatom IC50=30nM pA2=8.3 IC50=5nM pA2=10.3 pKi=8.7nM pA2=8.82 pKi=0.76nM pA2=10.1~10.7 Chemical modifications on biphenyl region Substitute of the near-end benzene ring Chemical modifications on biphenyl region Substitute of the near-end benzene ring Chemical modifications on biphenyl region Substitute of the far-end benzene ring IC50=6.9nM T1/2=0.68-1h IC50=5.2nM F=91% Chemical modifications on biphenyl region Substitute of the far-end benzene ring IC50=9.8nM pA2=8.4 Chemical modifications on biphenyl region Substitute of biphenyl Chemical modifications on biphenyl region Substitute of biphenyl IC50=0.8nM IC50=1.0nM Chemical modifications on biphenyl region Substitute of biphenyl Substitute of tetrazole Others NO-satan Others 72% 48% 生物利用度 生物半衰期 药物比较 AT1 亲和力 Comparison of ARB pharmacokinetics 洛沙坦 缬沙坦 坎地沙坦 伊贝沙坦 名称 Losartan Valsartan Candesartan cilexetil Irbesartan 商品名 Cozaar Diovan Atacand Aprovel 半衰期 2.2h 2-4h 9h 11-15h 常用剂量 50-100mg/d 80-320mg/d 4-32mh/d 150-300mg/d 生物利用度 30% 23% 42% 60-80% 化学结构分类 联苯四氮唑类 非杂环类 联苯四氮唑类 联苯四氮唑类 血药浓度达峰时间 3-4h 2