• Proceedings of the Korean Society of Food Hygiene and Safety Conference
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• 2004.05a
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• pp.231-231
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• 2004

• Archives of Pharmacal Research
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• v.22 no.4
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• pp.372-379
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• 1999

A series of disubstituted 4,5-polymethylenepyrazoles were synthesized and evaluated their inhibitory activities against COX-2. Some compounds showed strong (0.3 nM) inhibitory activity on COX-2 and were found somewhat selective (up to 16) on COX-2 over COX-1.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.347.4-348
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• 2002

Recently it has been demonstrated that selective cyclooxygenase-2 (COX-2) inhibitors retain the antiinflammatory effect but with markedly reduced GI toxicity compared to non selective inhibitors such as traditional NSAIDs. As a consequence, intense efforts have been made to develop selective COX-2 inhibtors during the last decade. Two compounds in this class. celecoxib and rofecoxib. are already in the market and are proved as potent and selective COX-2 inhibitors with much better gastric tolerance. However. there are still strong domands for a COX-2 inhibitor with improved efficacy and safety profiles. Here we report the synthesis and biological profiles of 1.5- and 4.5-disubstituted imidazole analogues as structural equivalents of cefecoxib and refecoxib. The imidazole analogues are overlapped well whth the 3D srructures of celecoxib and rofecoxib.

• 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.

• Biomolecules & Therapeutics
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• v.20 no.2
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• pp.214-219
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• 2012

This research was designed to determine what components of Gardenia jasminoides play a major role in inhibiting the enzymes related antidepressant activity of this plant. In our previous research, the ethyl acetate fraction of G. jasminosides fruits inhibited the activities of both monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B), and oral administration of the ethanolic extract slightly increased serotonin concentrations in the brain tissues of rats and decreased MAO-B activity. In addition, we found through in vitro screening test that the ethyl acetate fraction showed modest inhibitory activity on dopamine-${\beta}$ hydroxylase (DBH). The bioassay-guided fractionation led to the isolation of five bio-active compounds, protocatechuic acid (1), geniposide (2), 6'-O-trans-p-coumaroylgeniposide (3), 3,5-dihydroxy-1,7-bis(4-hydroxyphenyl) heptanes (4), and ursolic acid (5), from the ethyl acetate fraction of G. jasminoides fruits. The isolated compounds showed different inhibitory potentials against MAO-A, -B, and DBH. Protocatechuic acid showed potent inhibition against MAO-B ($IC_{50}$ $300{\mu}mol/L$) and DBH ($334{\mu}mol/L$), exhibiting weak MAO-A inhibition (2.41 mmol/L). Two iridoid glycosides, geniposide ($223{\mu}mol/L$) and 6'-O-trans-p-coumaroylgeniposide ($127{\mu}mol/L$), were selective MAO-B inhibitor. Especially, 6'-O-trans-p-coumaroylgeniposide exhibited more selective MAO-B inhibition than deprenyl, well-known MAO-B inhibitor for the treatment of early-stage Parkinson's disease. The inhibitory activity of 3,5-dihydroxy-1,7-bis (4-hydroxyphenyl) heptane was strong for MAO-B ($196{\mu}mol/L$), modest for MAO-A ($400{\mu}mol/L$), and weak for DBH ($941{\mu}mol/L$). Ursolic acid exhibited significant inhibition of DBH ($214{\mu}mol/L$), weak inhibition of MAO-B ($780{\mu}mol/L$), and no inhibition against MAO-A. Consequently, G. jasminoides fruits are considerable for development of biofunctional food materials for the combination treatment of depression and neurodegenerative disorders.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.3
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• pp.257-262
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• 2015

It is well known that cigarette smoke can cause erectile dysfunction by affecting the penile vascular system. However, the exact effects of nicotine on the corpus cavernosum remains poorly understood. Nicotine has been reported to cause relaxation of the corpus cavernosum; it has also been reported to cause both contraction and relaxation. Therefore, high concentrations of nicotine were studied in strips from the rabbit corpus cavernosum to better understand its effects. The proximal penile corpus cavernosal strips from male rabbits weighing approximately 4 kg were used in organ bath studies. Nicotine in high concentrations ($10^{-5}{\sim}10^{-4}M$) produced dose-dependent contractions of the corpus cavernosal strips. The incubation with $10^{-5}M$ hexamethonium (nicotinic receptor antagonist) significantly inhibited the magnitude of the nicotine associated contractions. The nicotine-induced contractions were not only significantly inhibited by pretreatment with $10^{-5}M$ indomethacin (nonspecific cyclooxygenase inhibitor) and with $10^{-6}M$ NS-398 (selective cyclooxygenase inhibitor), but also with $10^{-6}M$ Y-27632 (Rho kinase inhibitor). Ozagrel (thromboxane $A_2$ synthase inhibitor) and SQ-29548 (highly selective TP receptor antagonist) pretreatments significantly reduced the nicotine-induced contractile amplitude of the strips. High concentrations of nicotine caused contraction of isolated rabbit corpus cavernosal strips. This contraction appeared to be mediated by activation of nicotinic receptors. Rho-kinase and cyclooxygenase pathways, especially cyclooxygenase-2 and thromboxane $A_2$, might play a pivotal role in the mechanism associated with nicotine-induced contraction of the rabbit corpus cavernosum.

• Journal of Applied Biological Chemistry
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• v.66
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• pp.165-170
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• 2023

Isolation of the culture broth of a marine-derived Acremonium sp. CNQ-049 guided by HPLC-UV yielded compound 1 (3-phenethyl-2-phenylquinazolin-4(3H)-one), and its inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and β-secretase 1 (BACE1) were evaluated. Compound 1 was an effective selective MAO-B inhibitor with an IC₅₀ value of 9.39 µM and a selectivity index (SI) value of 4.26 versus MAO-A. In addition, compound 1 showed a potent selective butyrylcholinesterase (BChE) inhibition with an IC₅₀ value of 7.99 µM and an SI value of 5.01 versus acetylcholinesterase (AChE). However, compound 1 showed weak inhibitions against MAO-A, AChE, and BACE1. The Ki value of compound 1 for MAO-B was 5.22±1.73 µM with competitive inhibition, and the Ki value of compound 1 for BChE was 3.00±1.81 µM with mixed-type inhibition. Inhibitions of MAO-B and BChE by compound 1 were recovered by dialysis experiments. These results suggest that compound 1 is a dual-functional reversible inhibitor of MAO-B and BChE, that can be used as a treatment agent for neurological disorders.

• Journal of Korean Society for Atmospheric Environment
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• v.18 no.E2
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• pp.121-128
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• 2002

This study was carried out to investigate if nitric oxide synthase (NOS) inhibitors modulate airway inflammation induced by diesel exhaust particles (DEP). N$\^$G/-nitro-L-arginine methyl ester (L-NAME), a potent constitutive NOS (cNOS) inhibitor, and aminoguanidine (AG), a selective inducible NOS (iNOS) inhibitor, were administered to mice in their drinking water for 7 weeks. Airway inflammation was elicited by the repeated intratracheal administration of DEP. The results showed that macrophages, inflammatory eosinophils and neutrophils in bronchoalveolar lavage (BAL) fluids by intratracheal DEP instillation were significantly suppressed in the mice treated with two NOS inhibitors toghther with DEP. The suppression of these cells was more effective in AG treated groups than in L -NAME treated groups. NOS inhibitor treatment also reduced interleukin -5 (IL-5 in the BAL fluids and lung homogenates. Additionally, it was found that eosinophil peroxidase (EPO) activity in the BAL fluids was also decreased by NOS inhibitor treatment. These results suggest that nitric oxide (NO) is produced in airway inflammation by repeated DEP instillation, and that iNOS inhibition as well as cNOS inhibition can play a modulating role in this airway inflammation by DEP.

• Biomolecules & Therapeutics
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• v.5 no.3
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• pp.228-232
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• 1997

AU-164 was synthesized as a reversible gastric $H^+/K^+$ ATPase inhibitor, and its effects were tested in various systems. AU-164 inhibited rabbit gastric $H^+/K^+$ ATPase with an $IC_{50}$/ of 9 $\mu$M. On the other hand, AU-164 was a weak inhibitor for dog kidney $Na^+/K^+$ ATPasc, indicating the selectivity for gastric $H^+/K^+$ ATPase. The reversible property of the AU-164-induced inhibition of $H^+/K^+$ ATPase was confirmed by filtering the inhibition mixture through Sephadex G-25M column. In vivo basal acid secretion was also inhibited by AU-164 under the pylorus ligation of Sprague-Dawley rats. In addition, AU-164 protected dose dependently gastric lesion induced by ethanol in rats. The $ED_{50}$ value of 62 mg/kg p.o was estimated. These results suggest that AU-164 is a potent, selective and reversible gastric $H^+/K^+$ ATPase inhibitor, and that AU-164 has a potential use for the clinical therapeutics of peptic ulcer disease.

• 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)