新型磷酸二酯酶特异性抑制剂的发现及识别机制
发布时间：2018-08-14 12:10
【摘要】：磷酸二酯酶(PDE)通过催化水解细胞内第二信使(环磷酸腺苷cAMP,或环磷酸鸟苷cGMP),以降低细胞内cAMP或cGMP的浓度,从而中止这两个第二信使所传导的生理作用。PDEs作为新型的药物作用靶点,参与多种疾病的治疗,已成为新药研发的重要靶点。截至目前,已有多个PDE抑制剂药物上市(PDE5:5个,治疗性功能障碍和肺动脉高压;PDE4:3个,治疗慢性阻塞性肺病等),其中最出名的案例是用于治疗男性勃起功能障碍和肺动脉高压的PDE5抑制剂西地那非。然而,低选择性是这些PDE抑制剂的主要缺陷。近期我们针对PDE4,5,8,9和10等亚型,通过基于结构的药物分子设计,合成并发现多类高选择性的抑制剂。如,1)合成近150个PDE9抑制剂,从中发现抑制效应最强的高选择性先导结构3r。3r(IC_(50)=0.6 nmol·L~(-1),对PDE1选择性为788倍),活性和选择性均明显优于临床Ⅱ期的辉瑞抑制剂PF-04447943。通过晶体结构分析,发现3r与PDE9特有残基Y424形成氢键,是其具有高倍选择性的结构基础,这为PDE9高选择性抑制剂提供了新的设计策略。此外共晶结构还揭示3r和A452形成一个氢键,而PF-04447943未显示这种结合模式。通过设计与A452形成氢键,可提高化合物的抑制效应。2)合成近100个多个PDE5抑制剂,从中发现抑制剂从中发现抑制效应最强的高选择性先导结构1610。1610(IC_(50)=5.0 nmol·L~(-1),对PDE6选择性为100倍)的抑制活性与辉瑞药物西地那非相当,但选择性均明显优于西地那非(对PDE6选择性为2~3倍),动物实验也显示该类药物的抗动脉高压效果明显优于对照药物西地那非。通过分子模拟分析,发现1610进入靶标结构的Q2口袋,是1610具有100倍选择性的结构基础,这为PDE5高选择性抑制剂提供了新的设计策略。
[Abstract]:Phosphodiesterase (PDE) reduces the concentration of cAMP or cGMP by catalyzing the hydrolysis of second messengers (camp, cyclic adenosine monophosphate), or guanosine cyclophosphate (cGMP), in cells. As a new drug target, PDEs is involved in the treatment of many diseases and has become an important target of new drug research and development. To date, several PDE inhibitors have been listed (PDE5: 5, PDE4: 3 for treatment of sexual dysfunction and pulmonary hypertension). One of the best known cases is sildenafil, an inhibitor of PDE5 used to treat erectile dysfunction and pulmonary hypertension in men. However, low selectivity is the main defect of these PDE inhibitors. Recently, we synthesized and discovered many kinds of highly selective inhibitors by structure-based drug molecular design for PDE4C5H8 / 9 and PDE4 / 10 subtypes. If 1) nearly 150 PDE9 inhibitors were synthesized, the highly selective leading structure 3r.3r (IC50) 0.6 nmol L ~ (-1) was found to have the strongest inhibitory effect, and the selectivity to PDE1 was 788-fold. The activity and selectivity of Pfizer inhibitor Pfizer (PF-04447943) were significantly better than that of Pfizer inhibitor Pfizer in phase 鈪，
本文编号：2182820
[Abstract]:Phosphodiesterase (PDE) reduces the concentration of cAMP or cGMP by catalyzing the hydrolysis of second messengers (camp, cyclic adenosine monophosphate), or guanosine cyclophosphate (cGMP), in cells. As a new drug target, PDEs is involved in the treatment of many diseases and has become an important target of new drug research and development. To date, several PDE inhibitors have been listed (PDE5: 5, PDE4: 3 for treatment of sexual dysfunction and pulmonary hypertension). One of the best known cases is sildenafil, an inhibitor of PDE5 used to treat erectile dysfunction and pulmonary hypertension in men. However, low selectivity is the main defect of these PDE inhibitors. Recently, we synthesized and discovered many kinds of highly selective inhibitors by structure-based drug molecular design for PDE4C5H8 / 9 and PDE4 / 10 subtypes. If 1) nearly 150 PDE9 inhibitors were synthesized, the highly selective leading structure 3r.3r (IC50) 0.6 nmol L ~ (-1) was found to have the strongest inhibitory effect, and the selectivity to PDE1 was 788-fold. The activity and selectivity of Pfizer inhibitor Pfizer (PF-04447943) were significantly better than that of Pfizer inhibitor Pfizer in phase 鈪，
本文编号：2182820
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