Phosphodiesterase type 5 (PDE5); PDE5 (IC50 = 2.28 nM); PDE6 (IC50 = 45.2 nM); PDE1 (IC50 = 566 nM); PDE4 (IC50 = 834 nM); PDE11 (IC50 = 6090 nM)
The primary target of TPN729MA is the PDE5 enzyme. It is a selective inhibitor of PDE5, showing high potency against this isoform with an IC50 of 2.28 nM. Its selectivity profile includes an IC50 of 45.2 nM for PDE6, 566 nM for PDE1, 834 nM for PDE4, and 6090 nM for PDE11, demonstrating its specificity for PDE5.

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)[1].

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In vitro, TPN729MA is a highly potent and selective PDE5 inhibitor. Its potency is demonstrated by an IC50 of 2.28 nM. This enzyme inhibition prevents the breakdown of cGMP, prolonging its signaling. In the context of erectile function, this leads to smooth muscle relaxation in the corpus cavernosum, increasing blood flow.

The intracavernous pressure/blood pressure ratio (ICP/BP) was elevated at all time points at the 5.0 mg/kg dose, 75, 90, 105, and 2.5 mg/kg by TPN729MA (1.25, 2.5, 5.0 mg/kg; 1 dose). elevated blood pressure to intracavernous pressure ratio at 120 minutes[1]. In male beagle dogs, TPN729MA (5.0 μg/kg; administered intravenously) dramatically raises both intracavernous pressure and the intracavernous pressure/blood pressure ratio[1].

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In vivo, TPN729MA (at doses of 1.25, 2.5, and 5.0 mg/kg) dose-dependently increases the maximum intracavernous pressure (ICP) and the ICP-to-blood pressure ratio in male Sprague-Dawley rats. In male beagle dogs, an intravenous dose of 5.0 microg/kg also dramatically raises both intracavernous pressure and the ICP/BP ratio.

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. In this study, researchers investigated the in vitro inhibitory potency and selectivity of TPN729MA on PDE isozymes. Methods: The inhibition of 11 human recombinant PDEs by TPN729MA, sildenafil, and tadalafil were determined using radioimmunoassay[1].

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As a PDE5 inhibitor, TPN729MA can be evaluated using a standard radiometric assay. Recombinant human PDE5 is incubated with 3H-cGMP and varying concentrations of the test compound for 20 minutes at room temperature. The reaction is stopped, and the 3H-5'-GMP product is measured using a scintillation proximity assay (SPA) to calculate the IC50.

While a detailed cell-based protocol for TPN729MA is not described, a standard method is to use HEK293 cells overexpressing PDE5. The cells are treated with increasing concentrations of the compound. After an incubation period, cells are lysed and a cGMP ELISA is performed. An increase in intracellular cGMP relative to the control indicates successful PDE5 inhibition.

Animal/Disease Models: Male SD (Sprague-Dawley) rats with corpora cavernosa complete exposure[1]
Doses: 1.25, 2.5 and 5.0 mg/kg
Route of Administration: Intraduodenal (id) injection; 1.25, 2.5 and 5.0 mg/kg, once
Experimental Results: Dose-dependently increased the maximum intracavernous pressure (ICP) and ICP/blood pressure (BP).

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For the rat in vivo study, male Sprague-Dawley rats are anesthetized. One carotid artery is cannulated for blood pressure (BP) measurement, and the corpus cavernosum is cannulated for intracavernous pressure (ICP) measurement. TPN729MA is administered intraduodenally (id) at doses of 1.25, 2.5, or 5.0 mg/kg. ICP and BP are continuously recorded for up to 2 hours post-administration. The ICP/BP ratio is calculated to assess efficacy.

No specific PK data for TPN729MA is provided. However, its in vivo efficacy in rat and dog studies, following intraduodenal and intravenous administration, suggests it is bioavailable via these routes. The text also mentions it may be an "orally active prodrug," implying that it is converted to its active form after absorption.

Standard toxicological data for TPN729MA is not provided. The in vivo studies in rats and dogs likely included monitoring for adverse effects during the short duration of the experiment. No serious adverse events such as significant hypotension or cardiac arrhythmias were reported in the described ICP/BP measurement studies.

[1]. Wang Z, et al. The selectivity and potency of the new PDE5 inhibitor TPN729MA. J Sex Med. 2013 Nov;10(11):2790-7.

TPN729MA is a newly developed phosphodiesterase type 5 (PDE5i) inhibitor for the treatment of erectile dysfunction. Compared with currently used clinical PDE5i, it has higher selectivity and a longer duration of action. Objective: We investigated the in vitro inhibitory efficacy and selectivity of TPN729MA against PDE isoenzymes, and its efficacy in animal models. Methods: The inhibitory effects of TPN729MA, sildenafil, and tadalafil on 11 human recombinant PDEs were determined by radioimmunoassay. The effects of TPN729MA and sildenafil on intracavernosal pressure (ICP), blood pressure (BP), and the ICP/BP ratio were measured in a rat model of electrically induced erection and a canine model of sodium nitroprusside injection-induced erection. Primary outcome measures: The primary outcome measures were the IC50 values of TPN729MA, sildenafil, and tadalafil for PDE1-PDE11; maximum intracavernosal pressure (ICP); blood pressure (BP); and the ICP/BP ratio. Results: The IC50 values of TPN729MA, sildenafil, and tadalafil for PDE5 were 2.28, 5.22, and 2.35 nM, respectively. TPN729MA showed selectivity of 248-fold, 366-fold, 20-fold, and 2671-fold for PDE1, PDE4, PDE6, and PDE11, respectively. TPN729MA showed excellent selectivity (>10,000-fold) for PDE2, 3, 7, 8, 9, and 10. In an erectile rat model, TPN729MA (5.0 and 2.5 mg/kg) significantly increased maximum intracavernosal pressure compared to the solvent group, while sildenafil had no such effect. At all time points, ICP/BP was significantly increased in the TPN729MA (5.0 mg/kg) group; ICP/BP was also significantly increased in the TPN729MA (2.5 mg/kg) group at 75, 90, 105 and 120 minutes; ICP/BP was also significantly increased in the sildenafil group at 75 and 90 minutes, compared with the solvent group. In the canine erectile model, both TPN729MA and sildenafil significantly increased ICP and ICP/BP, but had no significant effect on BP compared with the solvent group. Conclusion: TPN729MA is a potent PDE5 inhibitor with balanced selectivity. TPN729MA has shown excellent efficacy in vitro and in vivo, and its effect on erectile function is more durable than that of sildenafil in animal models. [1]

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TPN729MA is a research compound that has been studied for its potential use in treating erectile dysfunction. Its high potency and selectivity for PDE5 over other PDE isoforms, particularly PDE6, are important characteristics as they reduce the potential for side effects like visual disturbances. The name "TPN729MA" suggests it is the maleate salt form of the active compound TPN729.

C29H40N6O8S

632.73

632.263

1422955-52-9

TPN729;936951-20-1

136266251

White to off-white solid powder

3

12

13

44

1010

0

CCCC1=NN(C2=C1N=C(NC2=O)C3=C(C=CC(=C3)S(=O)(=O)N(C)CCN4CCCC4)OCCC)C.C(=C\\C(=O)O)\\C(=O)O

CNCJOFPBSNINND-BTJKTKAUSA-N

InChI=1S/C25H36N6O4S.C4H4O4/c1-5-9-20-22-23(30(4)28-20)25(32)27-24(26-22)19-17-18(10-11-21(19)35-16-6-2)36(33,34)29(3)14-15-31-12-7-8-13-31;5-3(6)1-2-4(7)8/h10-11,17H,5-9,12-16H2,1-4H3,(H,26,27,32);1-2H,(H,5,6)(H,7,8)/b;2-1-

(Z)-but-2-enedioic acid;N-methyl-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-propoxy-N-(2-pyrrolidin-1-ylethyl)benzenesulfonamide

TPN-729 maleate; TPN729 maleate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 25 mg/mL (39.51 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.95 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)