中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
Pharmacokinetics-Driven Optimization of 4(3H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension

文献类型：期刊论文

作者Wang, Zhen1; Jiang, Xiangrui1; Zhang, Xianglei1,2; Tian, Guanghui3; Yang, Rulei3; Wu, Jianzhong3; Zou, Xiaoli3; Liu, Zheng4; Yang, Xiaojun4; Wu, Chunhui4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-05-23
卷号62期号:10页码:4979-4990
ISSN号0022-2623
DOI10.1021/acs.jmedchem.9b00123
通讯作者Jiang, Hualiang(hljiang@simm.ac.cn) ; Xu, Yechun(ycxu@simm.ac.cn) ; Shen, Jingshan(shenjingshan@simm.ac.cn)
英文摘要Phosphodiesterase type 5 (PDES) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylamino-phenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.
WOS关键词SELECTIVE PDE5 INHIBITOR ; SILDENAFIL ; TADALAFIL ; COMBINATION ; DISCOVERY ; THERAPY ; DESIGN
资助项目Strategic Priority Research Program of Chinese Academy of Sciences[XDA12040103] ; National Key R&D Program of China[2016YFA0502301] ; Scientific and Technological Innovation Program of Science and Technology Commission of Shanghai Municipality[16431900600] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; National Natural Science Foundation of China[81422047]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000469304500010
源URL[http://119.78.100.183/handle/2S10ELR8/289704]  
专题中国科学院上海药物研究所
通讯作者Jiang, Hualiang; Xu, Yechun; Shen, Jingshan
作者单位1.Chinese Acad Sci, Shanghai Inst Materia Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
3.Vigonvita Life Sci Co Ltd, Suzhou 215123, Peoples R China
4.Topharman Shanghai Co Ltd, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Plant Resources & Chem Arid Reg, Urumqi 830011, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Zhen,Jiang, Xiangrui,Zhang, Xianglei,et al. Pharmacokinetics-Driven Optimization of 4(3H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(10):4979-4990.
APA Wang, Zhen.,Jiang, Xiangrui.,Zhang, Xianglei.,Tian, Guanghui.,Yang, Rulei.,...&Shen, Jingshan.(2019).Pharmacokinetics-Driven Optimization of 4(3H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension.JOURNAL OF MEDICINAL CHEMISTRY,62(10),4979-4990.
MLA Wang, Zhen,et al."Pharmacokinetics-Driven Optimization of 4(3H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension".JOURNAL OF MEDICINAL CHEMISTRY 62.10(2019):4979-4990.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。