• Archives of Pharmacal Research
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• v.12 no.4
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• pp.276-281
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• 1989

Selective inhibition of seven new PDE inhibitors on cyclic nucleotide PDE isozymes was investigated. Three PDE isozymes (PDE I, II and III) of guinea pig left ventricular muscles were used. All tested agents inhibited cyclic AMP hydrolysis by PDE III IN A concentration-dependent manner. Some agents represented more potent and selective inhibitory effect on PDE III than that of imazodan.

• Childhood Kidney Diseases
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• v.6 no.1
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• pp.85-91
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• 2002

Purpose: Phosphodiesterase (PDE) inhibitor increases the cellular content of cAMP, and cAMP suppresses connective tissue growth factor (CTGF) expression induced by TGF-${\beta}1$. Therefore, we investigated whether PDE inhibitor suppresses renal fibrosis without suppression of TGF-${\beta}1$. Materials and Methods : Renal interstitial fibrosis was produced by ligation of left ureter in Sprague-Dawley rats. Cilostazol, a selective PDE3 inhibitor, and dipyridamole, a hybrid PDE5, PDE6, and PDE8 inhibitor, were provided in drinking water for 7 days. In addition to the Masson-trichrome score of renal tissue, the concentration of fibronectin and TGF-${\beta}1$ in renal tissue- conditioned media was measured by ELISA. Results : Masson- trichrome score and fibronectin concentration were significantly lower in cilostazol-treated group compared to the control group (P<0.05). Though dipyridamole treatment seemed to suppress the Masson- trichrome score and fibronectin concentration too, the decrements were not statistically significant. There was no difference in TGF-${\beta}1$ concentration among the groups. Conclusion: A selective PDE3 inhibitor cilostazol suppresses renal fibrosis without alteration of TGF-${\beta}1$ expression. (J Korean Soc Pediatr Nephrol 2002 ;6 : 85-91)

• 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.

• YAKHAK HOEJI
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• v.51 no.4
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• pp.235-238
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• 2007

To determine the regulatory roles of phosphodiesterase (PDE) inhibitors on $PGE_2$-induced osteoclastogenesis, we investigated the effect of PDE inhibitors on osteoclast formation in the presence of $PGE_2$. Among PDE isozyme specific inhibitors, milrinone, a selective PDE3 inhibitor, and rolipram, a specific PDE4 inhibitor, increased $PGE_2$-induced osteoclast formation in cocultures of mouse bone marrow cells and osteoblasts. To verify that whether the PDE3 and PDE4 inhibitors act indirectly on osteoblasts, we measured the concentration of intracellular cAMP in osteoblasts. Treatment of milrinone or rolipram increased $PGE_2$-stimulated cAMP levels in osteoblasts. Furthermore, northern blot analysis revealed that the PDE3 and PDE4 inhibitors works synergistically with $PGE_2$ to increase the expression of TRANCE mRNA in osteoblasts. On the contrary, the PDE3 and PDE4 inhibitors did not augment the number of osteoclasts differentiated from bone marrow cells by $PGE_2$. In conclusion, the stimulation of $PGE_2$-induced osteoclast formation by the PDE3 and PDE4 inhibitors are attributable to their indirect effect on osteoblasts, not to their direct effect on bone marrow-derived osteoclast precursors.

• 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)

• Biomolecules & Therapeutics
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• v.10 no.2
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• pp.117-123
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• 2002

CJ-10882, (E)-[(3-Cyclopentyloxy-4-methoxyphenyl)methylene]hydrazine-carboxamide, is a newly developed type IV phosphodiesterase isozyme (PDE IV) inhibitor. To investigate the subacute toxic effects of CJ-10882, it was administered to both male and female dogs at 0, 25, 50, 100 or 200 mg/kg/day orally for up to 2 weeks. During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross finding, organ weight, and histopathology were evacuated. Several clinical signs were observed in treated dogs at above 25 mg/kg, including salivation and vomiting. A reduction in the body weight was observed in both sexes at above 50 mg/kg. There were no treatment-related effects on mortality, ophthalmoscopy, urinalysis, hematology, sect biochemistry, necropsy findings, and histopathology in any treatment group. The results of this study demonstrate that CJ-10882, a selective Inhibitor of the type IV class of PDE, may cause effects on gastrointestinal tract and salivary glands. Therefore, these organs should be closely examined in studies with other PDE IV inhibitors.

• Mass Spectrometry Letters
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• v.6 no.2
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• pp.38-42
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• 2015

Roflumilast analogs are a group of drugs which act as selective photodiesterase (PDE-4) inhibitor for the treatment severe chronic pulmonary disease associated with chronic brochnonities. Structural identification of degradation products using high resolution mass spectrometry and theoretical investigation by density functional theory have been successfully carried out on roflumilast to identify four degradation products namely, 3,5-dichloropyridin-4-amine, N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-hydroxy benzamide, N-(3,5-dichloropyridin-4-yl)-3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzamide and 3-(cyclopropylmethoxy)-N-(3,5-dichloro-1-oxidopyridin-4-yl)-4-(difluoro methoxy) benzamide, generated in alkali, acidic and oxidative conditions.

• 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)

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.250.2-251
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• 2002

DA-8159 is a new. highly selective. potent cyclic-GMP phosphodiesterase 5 inhibitor developed by Dong-A Pharmaceutical Company(Kyunggi, Korea) as an oral drug for the treatment of erectile dysfunction. NO- cGMP signal transduction pathway plays a key role for relaxation of corpus cavernosal smooth muscle. In this study. the efficacy of DA-8159 was evaluated by measuring the length of uncovered penile mucosa in spinal cord injury(SCI) rabbits. (omitted)

• Proceedings of the Korean Society of Applied Pharmacology
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• 2002.07a
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• pp.232-232
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• 2002