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, Z (Wang, Zhen)[ 1 ]; Jiang, XR (Jiang, Xiangrui)[ 1 ]; Zhang, XL (Zhang, Xianglei)[ 1,2 ]; Tian, GH (Tian, Guanghui)[ 3 ]; Yang, RL (Yang, Rulei)[ 3 ]; Wu, JZ (Wu, Jianzhong)[ 3 ]; Zou, XL (Zou, Xiaoli)[ 3 ]; Liu, Z (Liu, Zheng)[ 4 ]; Yang, XJ (Yang, Xiaojun)[ 4 ]; Wu, CH (Wu, Chunhui)[ 4 ] |
刊名 | JOURNAL OF MEDICINAL CHEMISTRY |
出版日期 | 2019 |
卷号 | 62期号:10页码:4979-4990 |
ISSN号 | 0022-2623 |
DOI | 10.1021/acs.jmedchem.9b00123 |
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记录号 | WOS:000469304500010 |
源URL | [http://ir.xjipc.cas.cn/handle/365002/5766] |
专题 | 新疆理化技术研究所_省部共建新疆特有药用资源利用重点实验室 新疆理化技术研究所_资源化学研究室 |
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, Z ,Jiang, XR ,Zhang, XL ,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, Z .,Jiang, XR .,Zhang, XL .,Tian, GH .,Yang, RL .,...&Shen, JS .(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, Z ,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:新疆理化技术研究所
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