Original ResearchThe Selectivity and Potency of the New PDE5 Inhibitor TPN729MA
Introduction
Phosphodiesterase 5 inhibitors (PDE5i) block the degradation of cyclic guanosine monophosphate (cGMP) in human smooth muscle, resulting in smooth muscle relaxation in blood vessels 1, 2. Sildenafil citrate, sold as Viagra, and Revatio, acts by inhibiting phosphodiesterase 5 (PDE5), and has successfully been used to treat erectile dysfunction (ED) and pulmonary arterial hypertension (PAH).
In mammals, 21 different PDE-encoding genes have been identified so far, classified in 11 families by virtue of their sequence characteristics and the enzymatic properties of their corresponding protein products. A high selectivity of the inhibitors for PDE5 is important as other PDE isozymes also play key regulatory roles in a number of systems and inhibition against PDE isozymes other than PDE5 may lead to undesirable off-target adverse events and the discontinuation of therapy 3, 4.
As cGMP is a key component of intracellular signaling and PDE5 is widely distributed in smooth muscle, corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach, extensive preclinical evidence has suggested that PDE5i could be effective in the treatment of many other diseases including essential hypertension, lower urinary tract symptoms, benign prostatic hyperplasia (BPH), gastrointestinal disorders, Raynaud's phenomenon, endothelial dysfunction, pain, stroke and memory enhancement, and cancer 5, 6. Many of these indications are best suited to chronic oral dosing and emphasize the need for highly selective inhibitors with extended duration of action.
Sildenafil, tadalafil, and vardenafil were the first generation and currently the most widely used PDE5i in the world. These drugs are well tested and widely prescribed, and are considered a first-line treatment for ED [7]. But no drug is perfect. Sildenafil and vardenafil show weak inhibition against PDE6 potentially causing visual disturbances in clinical use [8]. Tadalafil causes back pain and myalgia, possibly owing to its inhibition of PDE11. Although PDE5i are generally regarded as safe and are used with minimal side effects, severe cardiovascular disorders and deaths have also been reported [9]. Some patients cannot bear these adverse effects and discontinue therapy. Avanafil is a new highly selective PDE5i approved by the Food and Drug Administration in 2012. Research has shown that avanafil is less likely to cause some of the more troubling side effects of the earlier PDE5i, such as “blue” vision, an unsafe drop in blood pressure when combined with nitroglycerine, or hearing loss 10, 11. However, it has a short terminal elimination half-life (Effective t1/2: 1.92–2.54 hours) [10] in healthy volunteers, not adequate for once daily dosing. Because of the unmet clinical needs with current PDE5i, research is ongoing to develop even better and safer alternatives.
We report a novel PDE5i, TPN729MA, its potency and inhibitory selectivity profile among PDE isozymes, and its efficacy in animal models. This compound offers potential for greater selectivity and longer duration of action than other currently available PDE5i.
Section snippets
Materials
TPN729MA (Figure 1) was synthesized by Topharman Shanghai Co., Ltd. (Shanghai, China). Sildenafil citrate was provided by Krka, d. d., Novo mesto (Novo mesto, Slovenia). Tadalafil was synthesized in house and its identity and purity were assessed by nuclear magnetic resonance, mass spectrometry, and high-performance liquid chromatography. Recombinant human PDE1-PDE11 were purchased from BPS Bioscience Inc. (San Diego, CA, USA). TRKQ7090 and TRKQ7100 PDE SPA assay kits were purchased from GE
In Vitro Activities and Selectivities
The IC50 values of TPN729MA, sildenafil, and tadalafil for the different isozymes are shown in Table 1. The IC50 values of TPN729MA, sildenafil, and tadalafil for PDE5 were 2.28, 5.22, and 2.35 nM, respectively. The selectivity of TPN729MA against PDE1 and PDE6 was higher than sildenafil (248 vs. 88-fold and 20 vs. eightfold) but lower than tadalafil (248 vs. 4894-fold and 20 vs. 171-fold). Both TPN729MA and sildenafil showed very weak inhibition against PDE4 (366 and 347-fold selectivity).
Discussion
As PDEs are expressed in a variety of tissues, selectivity is a prerequisite for a therapeutically applicable PDE5i. Inhibition of PDE1, mainly expressed in the brain, myocardium, and vascular smooth muscle cells, may result in vasodilation and tachycardia. Inhibition of PDE6, which is expressed only in retina and functions in visual transduction, can transiently disturb vision. Inhibition of PDE3, found predominantly in smooth muscles, platelets, and cardiac tissue, may elevate heart rate and
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 models.
Category 1
- (a)
Conception and Design
Zhen Wang; Jianfeng Li; Guanghui Tian; Qiaojun He; Bo Yang; Jingshan Shen
- (b)
Acquisition of Data
Zhen Wang; Difeng Zhu; Xiaochun Yang; Jie Jin; Honghai Wu; Qiaojun He; Bo Yang
- (c)
Analysis and Interpretation of Data
Zhen Wang; Difeng Zhu; Xiaochun Yang; Xiangrui Jiang; Nicholas Kenneth Terrett; Qiaojun He; Bo Yang; Jingshan Shen
Category 2
- (a)
Drafting the Article
Zhen Wang; Difeng Zhu; Xiaochun Yang; Jianfeng Li; Xiangrui Jiang; Jie Jin; Nicholas Kenneth Terrett; Bo Yang
- (b)
Revising It for Intellectual
Acknowledgments
This work has been funded by the National Science and Technology Major Project (No. 2009ZX09102-056 and 2012ZX09301001-001), the National High Technology Research and Development Program of China (2007AA02Z145 and 2012AA020302), the Key Project of Shanghai Science and Technology Commission for Fundamental Research and Development (no. 12431901702), the Innovation Fund for Technology Based Firms of Shanghai City (No. 1002H117400).
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2018, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :Therefore, PDE5 inhibitors can be used to treat ED effectively. TPN729 maleate (TPN729MA) is a novel PDE5 inhibitor, which was chemically synthesized by Topharman Shanghai Co., Ltd. (Shanghai, China) [4], and TPN729 was the free form of TPN729MA. Pre-clinical in vitro and in vivo pharmacodynamic studies suggested that TPN729 was a potent and specific inhibitor for PDE5 with an IC50 of 2.28 nM, which was lower than that of sildenafil (5.22 nM) and similar to that of tadalafil (2.35 nM) [4].
Innovative trends and perspectives for erectile dysfunction treatment: A systematic review
2016, Arab Journal of UrologyCitation Excerpt :They found that TPN729MA had good preclinical pharmacokinetics and showed the benefits of using a physiologically based pharmacokinetic model to predict pharmacokinetics in humans. Meanwhile, Wang et al. (2013) [12] investigated the in vitro inhibitory potency and selectivity of TPN729MA on PDE isozymes and its efficacy in rat and dog models, they concluded that TPN729MA is a potent PDE5I with a balanced selectivity profile. TPN729MA showed excellent potency both in vitro and in vivo and a longer effect on erectile function than sildenafil in the rat and dog models.
Characterization of TPN729 metabolites in humans using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry
2016, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :Preliminary pharmacokinetics of TPN729 in animals and humans has recently been reported [2]. As a potent inhibitor for PDE5 with an IC50 of 2.28 nM, TPN729 exerts its biological effects by selectively inhibiting PDE5 and blocking the degradation of cyclic guanosine monophosphate [1]. Currently available PDE5 inhibitors include sildenafil, vardenafil, and tadalafil (Fig. 1).
Conflict of Interest: Guanghui Tian and Jie Jin: Employes of Vitargeta. Nicholas Kenneth Terrett: advisor of Vitargeta. The rest of the authors declare no conflict of interest.