The Selectivity and Potency of the New PDE5 Inhibitor TPN729MA

doi:10.1111/jsm.12285

	The Selectivity and Potency of the New PDE5 Inhibitor TPN729MA
	Wang, Zhen1,2 ; Zhu, Difeng 1; Yang, Xiaochun 1; Li, Jianfeng2 ; Jiang, Xiangrui2 ; Tian, Guanghui 3; Terrett, Nicholas Kenneth 3; Jin, Jie 3; Wu, Honghai 1; He, Qiaojun 1
刊名	JOURNAL OF SEXUAL MEDICINE
	2013-11
卷号	10 期号:11 页码:2790-2797
关键词	Erectile Dysfunction Phosphodiesterase 5 Inhibitors Pharmacology Cyclic Guanosine Monophosphate Selectivity and Potency
ISSN号	1743-6095
DOI	10.1111/jsm.12285
文献子类	Article
英文摘要	IntroductionTPN729MA is a newly developed phosphodiesterase type 5 inhibitor (PDE5i) for the treatment of erectile dysfunction, which offers potential for greater selectivity and longer duration of action than PDE5i in current clinical use. AimWe investigated the in vitro inhibitory potency and selectivity of TPN729MA on PDE isozymes, and its efficacy in animal models. MethodsThe inhibition of 11 human recombinant PDEs by TPN729MA, sildenafil, and tadalafil were determined using radioimmunoassay. The effect of TPN729MA and sildenafil on intracavernous pressure (ICP), blood pressure (BP), and ICP/BP ratio were determined in a rat model of erection induced by electric stimulation and in a dog model of erection induced by sodium nitroprusside injection. Main Outcome MeasuresThe main outcome measures were IC50 of TPN729MA, sildenafil, and tadalafil for PDE1-PDE11; maximum ICP; BP and ICP/BP ratio. ResultsThe IC50 of TPN729MA, sildenafil, and tadalafil for PDE5 was 2.28, 5.22, and 2.35nM, respectively. TPN729MA showed 248, 366, 20, and 2671-fold selectivity against PDE1, PDE4, PDE6, and PDE11, respectively. TPN729MA showed excellent selectivity against PDE2, 3, 7, 8, 9, and 10 (>10,000-fold). In the rat model of erection, TPN729MA (5.0 and 2.5mg/kg), but not sildenafil, significantly increased the maximum ICP compared with vehicle. Significantly increased ICP/BP was observed in the TPN729MA (5.0mg/kg) group at all time points, in the TPN729MA (2.5mg/kg) group at 75, 90, 105, and 120 minutes time points, and in sildenafil group at 75 and 90 minutes time points compared with vehicle. In the dog model of erection, TPN729MA and sildenafil significantly increased ICP and ICP/BP but showed no significant effect on BP compared with vehicle. ConclusionsTPN729MA is a potent PDE5i with a balanced selectivity profile. TPN729MA shows excellent in vitro and in vivo potency, and a longer effect on erectile function than sildenafil in animal model. Wang Z, Zhu D, Yang X, Li J, Jiang X, Tian G, Terrett NK, Jin J, Wu H, He Q, Yang B, and Shen J. The selectivity and potency of the new PDE5 Inhibitor TPN729MA. J Sex Med 2013;10:2790-2797.
资助项目	National Science and Technology Major Project[2009ZX09102-056] ; National Science and Technology Major Project[2012ZX09301001-001] ; National High Technology Research and Development Program of China[2007AA02Z145] ; National High Technology Research and Development Program of China[2012AA020302] ; Key Project of Shanghai Science and Technology Commission for Fundamental Research and Development[12431901702] ; Innovation Fund for Technology Based Firms of Shanghai City[1002H117400]
WOS关键词	ERECTILE DYSFUNCTION ; PHOSPHODIESTERASE-5 INHIBITOR ; IN-VITRO ; PHARMACOKINETICS ; SILDENAFIL ; AVANAFIL ; DRUG ; RAT ; DOG
WOS研究方向	Urology & Nephrology
语种	英语
出版者	WILEY-BLACKWELL
WOS记录号	WOS:000326465900019
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277403]
专题	药物化学研究室
通讯作者	Yang, Bo
作者单位	1.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.Vitargeta Therapeut Inc, Plainsboro, NJ USA
推荐引用方式 GB/T 7714	Wang, Zhen,Zhu, Difeng,Yang, Xiaochun,et al. The Selectivity and Potency of the New PDE5 Inhibitor TPN729MA[J]. JOURNAL OF SEXUAL MEDICINE,2013,10(11):2790-2797.
APA	Wang, Zhen.,Zhu, Difeng.,Yang, Xiaochun.,Li, Jianfeng.,Jiang, Xiangrui.,...&Shen, Jingshan.(2013).The Selectivity and Potency of the New PDE5 Inhibitor TPN729MA.JOURNAL OF SEXUAL MEDICINE,10(11),2790-2797.
MLA	Wang, Zhen,et al."The Selectivity and Potency of the New PDE5 Inhibitor TPN729MA".JOURNAL OF SEXUAL MEDICINE 10.11(2013):2790-2797.