The selectivity and potency of the new PDE5 inhibitor TPN729MA.
BACKGROUND
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.


OBJECTIVE
We investigated the in vitro inhibitory potency and selectivity of TPN729MA on PDE isozymes, and its efficacy in animal models.


METHODS
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.


METHODS
The main outcome measures were IC50 of TPN729MA, sildenafil, and tadalafil for PDE1-PDE11; maximum ICP; BP and ICP/BP ratio.


RESULTS
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.


CONCLUSIONS
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.
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.
Zhen
Z
Wang
Difeng
D
Zhu
Xiaochun
X
Yang
Jianfeng
J
Li
Xiangrui
X
Jiang
Guanghui
G
Tian
Nicholas Kenneth
NK
Terrett
Jie
J
Jin
Honghai
H
Wu
Qiaojun
Q
He
Bo
B
Yang
Jingshan
J
Shen
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D004285:Dogs; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D000068581:Tadalafil
D002243:Carbolines; D007527:Isoenzymes; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009599:Nitroprusside; D000068581:Tadalafil; D000068677:Sildenafil Citrate
Cyclic Guanosine Monophosphate;Selectivity and Potency; Erectile Dysfunction; Pharmacology; Phosphodiesterase 5 Inhibitors