| Reference | 1. Antivir Chem Chemother. 2009 Sep 25;20(1):47-54. doi: 10.3851/IMP1372.
<br>
Anti-bovine viral diarrhoea virus and hepatitis C virus activity of the
cyclooxygenase inhibitor SC-560.
<br>
Okamoto M(1), Sakai M, Goto Y, Salim MT, Baba C, Goto K, Watashi K, Shimotohno K,
Baba M.
<br>
Author information: <br>
(1)Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases,
Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima,
Japan.
<br>
BACKGROUND: A number of compounds were examined for their inhibitory effect on
bovine viral diarrhoea virus (BVDV) replication in cell cultures and found that
some cyclooxygenase (COX) inhibitors had antiviral activity against the virus.
METHODS: Determination of compounds for their anti-BVDV activity was on the basis
of the inhibition of virus-induced cytopathogenicity in Mardin-Darby bovine
kidney (MDBK) cells. Anti-hepatitis C virus (HCV) activity was assessed by the
inhibition of viral RNA synthesis in the subgenomic HCV RNA replicon cells.<br>
RESULTS: Among the test compounds,
5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560)
was the most active against BVDV, and its 50% effective and cytotoxic
concentrations were 10.9 +/-2.8 and 93.9 +/-24.5 microM in virus and
mock-infected MDBK cells, respectively. The compound also suppressed BVDV RNA
synthesis in a dose-dependent fashion. Studies on the mechanism of action
revealed that SC-560 did not interfere with viral entry to the host cells.
Furthermore, it was assumed that the antiviral activity of SC-560 was not
associated with its inhibitory effect on COX. The combination of SC-560 and
interferon-alpha was additive to synergistic in inhibiting BVDV replication. More
importantly, the compound proved to be a selective inhibitor of HCV replication.
CONCLUSIONS: SC-560 and its derivative might have potential as novel antiviral
agents against HCV.
<br>
2. Int J Mol Med. 2006 Feb;17(2):245-52.
<br>
The selective cyclooxygenase-1 inhibitor SC-560 suppresses cell proliferation and
induces apoptosis in human hepatocellular carcinoma cells.
<br>
Lampiasi N(1), Foderà D, D/’Alessandro N, Cusimano A, Azzolina A, Tripodo C,
Florena AM, Minervini MI, Notarbartolo M, Montalto G, Cervello M.
<br>
Author information: <br>
(1)Istituto di Biomedicina e Immunologia Molecolare /’Alberto Monroy, C.N.R.,
Palermo, Italy.
<br>
Two isoforms of cyclooxygenase (COX) are known, and to date most studies have
implicated COX-2 in the development and progression of various human cancers.
Increasing evidence suggests that COX-1 may also play a similar role. Indeed, we
have recently observed that the dual COX-1/COX-2 inhibitor indomethacin induces
apoptosis in human hepatocellular carcinoma (HCC) cell lines more effectively
than the selective COX-2 inhibitors, possibly implicating COX-1 in HCC. In this
study we investigated the expression of COX-1 in non-tumor and malignant human
liver tissues, as well as the effects of the highly selective COX-1 inhibitor
SC-560 on cell growth and apoptosis in human HCC cell lines. Expression of COX-1
was detected in nearly all the samples assayed, although with a high variability
between non-tumoral (NT) and malignant tissues. The percentage of COX-1 positive
cells was significantly higher in the NT tissues than in the tumors (p<0.0001).
In well-differentiated HCC COX-1 expression was significantly higher than in the
poorly-differentiated tissues (p<0.05). SC-560 showed a dose- and time-dependent
inhibitory effect on HCC cell growth. The combination of the COX-1 inhibitor with
nimesulide and CAY10404, two selective COX-2 inhibitors, resulted in additive
effects on cell growth inhibition. SC-560 also inhibited colony formation in soft
agar and induced apoptosis in HCC cells in a dose-dependent manner. Moreover,
SC-560 decreased the levels of the anti-apoptotic proteins survivin and XIAP and
activated caspase-3 and -7 in a dose- and time-dependent fashion. In conclusion,
we report for the first time that the selective COX-1 inhibitor SC-560 exhibits
anti-tumor and apoptotic effects in human HCC cells. Overall, our previous and
present results suggest that both COX-1 and COX-2 inhibitors may have potential
therapeutic implications in HCC patients.
<br>
3. J Pharm Pharm Sci. 2003 May-Aug;6(2):205-10.
<br>
Formulation dependent pharmacokinetics, bioavailability and renal toxicity of a
selective cyclooxygenase-1 inhibitor SC-560 in the rat.
<br>
Teng XW(1), Abu-Mellal AK, Davies NM.
<br>
Author information: <br>
(1)Department of Pharmaceutial Sciences, College of Pharmacy, Washington State
University, Pullman, Washington 99164-6534, USA.
<br>
PURPOSE: To delineate formulation dependent pharmacokinetics and bioavailability
of SC-560, a relatively new cycloooxygenase-1 (COX-1) specific inhibitor, in the
rat and examine its influence on the renal tubular enzyme,
N-acetyl-beta-D-glucosaminidase (NAG), and urinary electrolytes.
METHODS: The pharmacokinetics of SC-560 was studied in Sprague-Dawley rats (n = 5
per group) after a single intravenous (i.v.) and oral dose (10 mg/kg) in
polyethylene glycol (PEG) 600 and a single oral dose (10 mg/kg) in 1%
methylcellulose (MC). Serial blood samples were collected via a catheter inserted
in the right jugular vein and serum samples were analysed for SC-560 using
reverse phase HPLC. After oral administration of SC-560 in PEG, urine was also
collected for 24 h and analysed for urinary sodium, chloride, and potassium as
well as NAG.<br>
RESULTS: After an iv dose (10 mg/kg) of SC-560, serum AUC, t(1/2), CL and Vd were
9704 +/- 4038 ng h/mL, 5.4 +/- 0.8 h, 1.15 +/- 0.46 L/h/kg and 9.1 +/- 4.6 L/kg
(mean +/- SD, n = 5), respectively. Oral administration of 10 mg/kg SC-560-PEG
and MC (n=5 rats) yielded serum AUC, C max, t (max )and t (1/2) of 1203.4 +/-
130.3 and 523 +/- 208 ng h/mL, 218.5 +/- 86.9 and 119.8 +/- 15.5 ng/mL, 1.00 +/-
1.8 and 2.0+/- 0 h, 3.7 +/- 1.6 and 2.7 +/- 1.7 h (mean +/- SD, n = 5),
respectively. A single oral dose 10 mg/kg of SC-560 in PEG resulted in an
increase in NAG excretion in urine and a reduction in 0-24 h urinary sodium,
potassium, and chloride excretion.<br>
CONCLUSIONS: SC-560 extensively distributes into rat tissues, and has a CL
approaching hepatic plasma flow. The drug displays low <15% and formulation
dependent bioavailability after oral administration and demonstrates kidney
toxicity.
<br>
|
