• Biomolecules & Therapeutics
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• v.11 no.1
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• pp.41-50
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• 2003

General pharmacological properties of DA-8159, a new pyrazolopyrimidinone derivative were examined in laboratory animals to investigate its safety profile. The oral administration of DA-8159 (1, 5 or 30 mg/kg) in mice and rats had no effect on general behaviors and central nervous system of the animals in test systems, such as hexobarbital-induced sleeping time, motor coordination, normal body temperature, writhing syndromes induced by 0.75% acetic acid solution, chemo-shock produced by pentetrazole solution and rotar rod test. Anesthetized cats treated intravenously with DA-8159 (0.1, 0.3, 1, 3 or 10 mg/kg) showed transient and mild decrease in blood pressure. However, heart rate, respiration rate and tidal volume were not changed by intravenous DA-8159. In the isolated organs including ileum, heart (sinus rate of atria and contractility of papillary muscle), trachea of guinea pigs and phrenic nerve of rats, DA-8159 ($10^{-8}$ ∼$10^{-5}$ mg/L) did not elicit any effect or inhibitory action on the chemically or electrically stimulated contraction. DA-8159 did not influence gastric secretion, pH and total acid output in rats and intestinal propulsion in mice. The administration of DA-8159 in rats had no effect on the platelet aggregation induced by ADP in rabbit plasma, urinary volume and electrolyte ion ($Na^{+}$, $K^{+}$, $Cl^{-}$) excretion in rats. Prothrombin time (PT) of the rats showed a mild but significant increase after administration of DA-8159. Activated partial thromboplastin time (APTT), however, was not affected by DA-8159. These results indicate that DA-8159 does not exert any of serious pharmacological effects.

• Archives of Pharmacal Research
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• v.26 no.8
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• pp.612-619
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• 2003

In this study, we evaluated the effects of oral administration of DA-8159, a selective phosphodiesterase-5 inhibitor, on the development of pulmonary hypertension (PH) induced by monocrotaline (MCT). Rats were administered either MCT (60 mg/kg) or saline. MCT-treated rats were divided into three groups and received orally administered vehicle, or 1 mg/kg or 5 mg/kg of DA-8159, twice a day for twenty-one days. The MCT group demonstrated increased right ventricular weights, medial wall thickening in the pulmonary arteries, myocardial fibrosis and the level of plasma cyclic guanosine monophosphate (cGMP), along with decreased body weight gains. However, DA-8159 markedly and dose-dependently reduced the development of right ventricular hypertrophy and medial wall thickening. DA-8159 also amplified the increase in plasma cGMP level and significantly increased the level of lung cGMP, compared with the MCT group. Although the body weight gain was still lower from the saline-treated control group, DA-8159 demonstrated a significant increase in body weight gains, in both 1 mg/kg and 5 mg/kg groups, when compared with the MCT group. In myocardial morphology, MCT-induced myocardial fibrosis was markedly prevented by DA-8159. These results suggest that DA-8159 may be a useful oral treatment option for PH.

• Archives of Pharmacal Research
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• v.25 no.6
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• pp.873-878
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• 2002

OA-8159, a new Phosphodiesterase (PDE) 5 inhibitor, has exhibited potent erectogenic potential in a penile erection test in rats and anesthetized dogs. In this study, we investigated the mechanism of its erectogenic activity by measuring the activity of OA-8159 against a various PDE isozymes and assessing cGMP and cAMP formation in a rabbit corpus cavernosum in vitro. DA-8159 inhibited the PDE 5 activity in rabbit and human platelets, which the $IC_{50}$ was 5.84$\pm$1.70 nM and 8.25$\pm$2.90 nM, respectively. The $IC_{50}$ of DA-8159 on PDE 1, PDE2, PDE 3 and PDE 6 were 870$\pm$57.4 nM, $101\pm$5 $\mu$M, 52.0$\pm$3.53 $\mu$M and 53.3$\pm$2.47 nM, respectively. This suggests that DA-8159 is a potent, highly selective, competitive inhibitor of PDE 5-catalyzed cGMP hydrolysis. The rates of cGMP hydrolysis catalyzed by human platelets-derived PDE 5 as a function of the cGMP concentration (5~100 nM) and two-fixed DA-8159 concentration (11.3 and 18.8 nM) were investigated in order to characterize the mode of PDE 5 inhibition by DA-8159. DA-8159 increased the apparent 4K_{m}$ value for cGMP hydrolysis but had no effect on the apparent $V_{max}$, indicating a competitive mode of inhibition. DA-8159 increased the cGMP concentrations in the rabbit corpus cavernosum dose dependently. In the presence of sodium nitroprusside (SNP), DA-8159 significantly sti\mulated the accu\mulation of cGMP when compared to the control level. This indicated that the enhancement of a penile erection by DA-8159 involved the relaxation of the cavernosal smooth \muscle by NO-sti\mulated cGMP accu\mulation. In conclusion, DA-8159 is a selective inhibitor of PDE 5-catalyzed cGMP hydrolysis and the enhancement of a penile erection by DA-8159 is mediated by the relaxation of the cavernosal smooth \muscle by the NO-sti\mulated cGMP accu\mulation.

• Archives of Pharmacal Research
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• v.23 no.5
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• pp.471-476
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• 2000

DA-8159, a new phosphodiesterase 5 inhibitor, was assessed for its erectogenic potential by a penile erection test in rats, the relaxation of isolated rabbit corpus cavernosum (CC), and estimation of the intracavernous pressure (ICP) in the anesthetized dog. Oral administration of DA-8159 (0.3 to 1 ${\mu}g/kg$ ) increased the number of erections in rats with increasing dosage, with the highest penile erection index at 10 ${\mu}g/kg$ DA-8159 induced the relaxation of phenylephrine (PHE)-induced contractions in the rabbit CC and decreased the $IC_{50}$ of the nitric oxide donor sodium nitroprusside (SNP) in a dose-dependent fashion. In pentobarbital-anesthetized dogs, the intravenous administration of DA-8159 (1~300 ${\mu}g/kg$ ) potentiated the increase in ICP induced by the intracavernosal SNP in a dose-related manner. These findings suggest that DA-8159 has significant therapeutic potential in the treatment of erectile dysfunction.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.245.1-245.1
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• 2003

DA-8159 is a new PDEV (Phosphodiesterase V) inhibitor, synthesized by Dong-A Pharm., as an oral agent to treat male erectile dysfunction. To make a selection of the dosage of oral administration in carcinogenic studies, we studied preliminarily the pharmacokinetics of DA-8159 after single (at the 1$\^$st/ day) and 1-week (at the 7$\^$th/ day) oral administrations of the drug at doses of 15, 50 and 150 mg/kg/day, to male ICR mice. In 15mg/kg single and 1-week repeated oral administration groups, the concentrations of DA-8159 and DA-8164(the main metabolite of DA-8159) were below the limit of quantitation(LOQ:50ng/ml). (omitted)

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.253.1-253.1
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• 2002

DA-8159 is a new PDEV inhibitor, synthesized by Dong-A Pharm, as an oral agent to treat male erectile dysfunction. DA-8159 and sildenafil are mainly metabolized by cytochrome P450 enzyme CYP 3A4. In this study. we compared the metabolism of DA-8159 with sildenafil in vitro and in vivo. First, we quantified the remaining gatio of original compound, DA-8159 and sidenafil., after we incubated drugs for 30 minutes with human liver microsome cytochrome P 450 3A4. (omitted)

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.250.1-250.1
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• 2002

DA-8159. a selective inhibitor of phosphodiesterase type 5 (PDE5: IC$\sub$50/ 5ng/$m\ell$). is being developed as a new treatment for erectile dysfunction. Since DA-8159 has been shown to inhibit PDE6 enzyme (IC$\sub$53ng/$m\ell$). we evaluated the effect of DA-8159 on electroretinogram (ERG) and retinal histopathology in rabbits. The effect of oral DA-8159 (5 to 30mg/kg) on ERG recordings was investigated at pre-treatment. 1 and 5 hrs after administration in rabbits. (omitted)

• Proceedings of the Korean Society of Toxicology Conference
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• 2002.11b
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• pp.202-202
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• 2002

DA-8159, a new pyrazolopyrimidinone derivative for erectile dysfunction, was administered by gavage at levels of 0, 17.5, 70, and 280 mg/mg to Sprague-Dawley male rats from 28 days before mating to the end of mating period, and to remales from 14 days before mating to day 6 of gestation.(omitted)

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2002.11a
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• pp.202-202
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• 2002

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.249.2-250
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• 2002

Tolerance and pharmacolinetics after single-dose administration of DA-8159, a new selective PDE5 inhibitor under phase 1 study, were examined in 42 healthy male volunteers in a six-period, double-blinded placebo-controlled study. Participants received single oral tablet of DA-8159 (12.5 to 300mg) or placebo. Adverse effects and pharmacokinetic parameters were monitored during experiments. DA-8159 was well tolerated and the frequency of adverse events was dose-related. (omitted)