Design, Synthesis, and Pharmacological Evaluation of Monocyclic Pyrimidinones as Novel Inhibitors of PDE5

doi:10.1021/jm301159y

	Design, Synthesis, and Pharmacological Evaluation of Monocyclic Pyrimidinones as Novel Inhibitors of PDE5
	Wang, Guan 2; Liu, Zheng 1; Chen, Tiantian 2; Wang, Zhen2 ; Yang, Huaiyu 2; Zheng, Mingyue2 ; Ren, Jing 2; Tian, Guanghui 1; Yang, Xiaojun 1; Li, Li 2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2012-12-13
卷号	55 期号:23 页码:10540-10550
ISSN号	0022-2623
DOI	10.1021/jm301159y
文献子类	Article
英文摘要	Cyclic nucleotide phosphodiesterase type 5 (PDES) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDES, resulting in 25 compounds with IC50 ranging from 1 to 100 nM and 11 compounds with IC50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]pyrimid-4(3H)-one, the most potent compound, has an excellent IC50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.
资助项目	"100 Talents Project" of CAS[00000000] ; National Science and Technology Major Project[2009ZX09102-056] ; National Science and Technology Major Project[2012ZX09301001-001] ; National High-Tech R&D Program (863 Program)[2007AA02Z145] ; National Natural Science Foundation of China[91013010] ; National Natural Science Foundation of China[21172233] ; Key Project of Shanghai Science and Technology Commission for Fundamental Research and Development[08JC1422400] ; Innovation Fund for Technology Based Firms of Shanghai City[1002H117400]
WOS关键词	ERECTILE DYSFUNCTION ; PHOSPHODIESTERASE-5 INHIBITORS ; STRUCTURAL BASIS ; IN-VITRO ; SILDENAFIL ; VARDENAFIL ; TADALAFIL ; POTENT ; PHARMACOKINETICS ; OPTIMIZATION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000312227300020
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277845]
专题	药物化学研究室药物发现与设计中心
通讯作者	Jiang, Hualiang
作者单位	1.Vitargeta Therapeut Inc, Plainsboro, NJ 08536 USA 2.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Wang, Guan,Liu, Zheng,Chen, Tiantian,et al. Design, Synthesis, and Pharmacological Evaluation of Monocyclic Pyrimidinones as Novel Inhibitors of PDE5[J]. JOURNAL OF MEDICINAL CHEMISTRY,2012,55(23):10540-10550.
APA	Wang, Guan.,Liu, Zheng.,Chen, Tiantian.,Wang, Zhen.,Yang, Huaiyu.,...&Jiang, Hualiang.(2012).Design, Synthesis, and Pharmacological Evaluation of Monocyclic Pyrimidinones as Novel Inhibitors of PDE5.JOURNAL OF MEDICINAL CHEMISTRY,55(23),10540-10550.
MLA	Wang, Guan,et al."Design, Synthesis, and Pharmacological Evaluation of Monocyclic Pyrimidinones as Novel Inhibitors of PDE5".JOURNAL OF MEDICINAL CHEMISTRY 55.23(2012):10540-10550.