College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
J Sex Med. 2013 Nov;10(11):2790-7. doi: 10.1111/jsm.12285. Epub 2013 Aug 12.
TPN729MA 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.
We investigated the in vitro inhibitory potency and selectivity of TPN729MA on PDE isozymes, and its efficacy in animal models.
The 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.
The main outcome measures were IC50 of TPN729MA, sildenafil, and tadalafil for PDE1-PDE11; maximum ICP; BP and ICP/BP ratio.
The IC50 of TPN729MA, sildenafil, and tadalafil for PDE5 was 2.28, 5.22, and 2.35 nM, 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 2.5 mg/kg), but not sildenafil, significantly increased the maximum ICP compared with vehicle. Significantly increased ICP/BP was observed in the TPN729MA (5.0 mg/kg) group at all time points, in the TPN729MA (2.5 mg/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.
TPN729MA 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.
TPN729MA 是一种新开发的磷酸二酯酶 5 抑制剂（PDE5i），用于治疗勃起功能障碍，与当前临床使用的 PDE5i 相比，它具有更高的选择性和更长的作用持续时间。
我们研究了 TPN729MA 对 PDE 同工酶的体外抑制效力和选择性，以及其在动物模型中的疗效。
使用放射免疫测定法测定 TPN729MA、西地那非和他达拉非对 11 种人重组 PDE 的抑制作用。在电刺激诱导勃起的大鼠模型和硝普钠注射诱导勃起的犬模型中，测定 TPN729MA 和西地那非对阴茎海绵体内压（ICP）、血压（BP）和 ICP/BP 比值的影响。
主要观察指标为 TPN729MA、西地那非和他达拉非对 PDE1-PDE11 的 IC50；最大 ICP；BP 和 ICP/BP 比值。
TPN729MA、西地那非和他达拉非对 PDE5 的 IC50 分别为 2.28、5.22 和 2.35nM。TPN729MA 对 PDE1、PDE4、PDE6 和 PDE11 的选择性分别为 248、366、20 和 2671 倍。TPN729MA 对 PDE2、3、7、8、9 和 10 的选择性>10000 倍。在大鼠勃起模型中，与载体相比，TPN729MA（5.0 和 2.5mg/kg）显著增加了最大 ICP。在 TPN729MA（5.0mg/kg）组的所有时间点，在 TPN729MA（2.5mg/kg）组的 75、90、105 和 120 分钟时间点，以及西地那非组的 75 和 90 分钟时间点，均观察到显著增加的 ICP/BP。在犬勃起模型中，TPN729MA 和西地那非均显著增加 ICP 和 ICP/BP，但与载体相比，对 BP 无显著影响。
TPN729MA 是一种有效的 PDE5i，具有平衡的选择性特征。TPN729MA 在体外和体内均表现出优异的效力，并且在动物模型中比西地那非具有更长的勃起功能作用。
