|
Binding affinity to human CBG receptor (corticosteroid-binding globulins)
|
None
|
13.18
nM
|
|
Journal : J. Med. Chem.
Title : Comparative molecular active site analysis (CoMASA). 1. An approach to rapid evaluation of 3D QSAR.
Year : 2004
Volume : 47
Issue : 11
First Page : 2732
Last Page : 2742
Authors : Kotani T, Higashiura K.
Abstract : We have developed a rapid evaluation method, comparative molecular active site analysis (CoMASA), for obtaining 3D QSAR. CoMASA has three major advantages: (1) the CoMASA results would easily transform to pharmacophore and/or queries required for 3D database searches, (2) the CoMASA method is not required to consider orientation and translation of molecules against a lattice, and (3) standard PCs can be used to perform the analysis. The potential of these improvements and possible further enhancements are discussed.
|
Compound was measured for its inhibitory activity on IFN-gamma-induced nitric oxide production in mouse macrophage
|
Mus musculus
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New enone derivatives of oleanolic acid and ursolic acid as inhibitors of nitric oxide production in mouse macrophages
Year : 1997
Volume : 7
Issue : 13
First Page : 1623
Last Page : 1628
Authors : Honda T, Finlay HJ, Gribble GW, Suh N, Sporn MB
|
Inhibitory activity against production of nitric oxide induced by interferon-gamma in mouse macrophages
|
Mus musculus
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel synthetic oleanane triterpenoids: a series of highly active inhibitors of nitric oxide production in mouse macrophages.
Year : 1999
Volume : 9
Issue : 24
First Page : 3429
Last Page : 3434
Authors : Honda T, Rounds BV, Bore L, Favaloro FG, Gribble GW, Suh N, Wang Y, Spor MB.
Abstract : Novel oleanane triterpenoids with modified rings A and C were designed and synthesized. Among them, methyl 2-carboxy-3,12-dioxooleana-1,9-dien-28-oate showed similar high inhibitory activity (IC50 = 0.8 nM) to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), which we have synthesized previously, against production of nitric oxide induced by interferon-gamma in mouse macrophages.
|
In vitro inhibitory activity on the production of nitric oxide (NO) induced by LPS in mouse peritoneal macrophages at a concentration of 10e-4 M
|
Mus musculus
|
92.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitory effect and action mechanism of sesquiterpenes from Zedoariae Rhizoma on D-galactosamine/lipopolysaccharide-induced liver injury.
Year : 1998
Volume : 8
Issue : 4
First Page : 339
Last Page : 344
Authors : Matsuda H, Ninomiya K, Morikawa T, Yoshikawa M.
Abstract : Hepatoprotective sesquiterpenes were isolated from the aqueous acetone extract of Zedoariae Rhizoma, the rhizome of Curcuma zedoaria ROSCOE (Zingiberaceae). Principal sesquiterpenes, furanodiene, germacrone, curdione, neocurdione, curcumenol, isocurcumenol, aerugidiol, zedoarondiol, and curcumenone and curcumin were found to show potent protective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver injury in mice. Plausible action mechanisms for their hepatoprotective activity were clarified on the basis of the inhibitory effect on D-GalN-induced cytotoxicity in primary cultured rat hepatocytes, LPS-induced NO production in cultured mouse peritoneal macrophages, and D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced liver injury in mice.
|
In vivo inhibitory activity on the increase of serum GOT induced by D-GalN / LPS (liver injury) in mice at 20 mg/kg peroral administration
|
Mus musculus
|
98.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitory effect and action mechanism of sesquiterpenes from Zedoariae Rhizoma on D-galactosamine/lipopolysaccharide-induced liver injury.
Year : 1998
Volume : 8
Issue : 4
First Page : 339
Last Page : 344
Authors : Matsuda H, Ninomiya K, Morikawa T, Yoshikawa M.
Abstract : Hepatoprotective sesquiterpenes were isolated from the aqueous acetone extract of Zedoariae Rhizoma, the rhizome of Curcuma zedoaria ROSCOE (Zingiberaceae). Principal sesquiterpenes, furanodiene, germacrone, curdione, neocurdione, curcumenol, isocurcumenol, aerugidiol, zedoarondiol, and curcumenone and curcumin were found to show potent protective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver injury in mice. Plausible action mechanisms for their hepatoprotective activity were clarified on the basis of the inhibitory effect on D-GalN-induced cytotoxicity in primary cultured rat hepatocytes, LPS-induced NO production in cultured mouse peritoneal macrophages, and D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced liver injury in mice.
|
In vivo inhibitory activity on the increase of serum GPT induced by D-GalN / LPS (liver injury) in mice at 50 mg/kg peroral administration
|
Mus musculus
|
99.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitory effect and action mechanism of sesquiterpenes from Zedoariae Rhizoma on D-galactosamine/lipopolysaccharide-induced liver injury.
Year : 1998
Volume : 8
Issue : 4
First Page : 339
Last Page : 344
Authors : Matsuda H, Ninomiya K, Morikawa T, Yoshikawa M.
Abstract : Hepatoprotective sesquiterpenes were isolated from the aqueous acetone extract of Zedoariae Rhizoma, the rhizome of Curcuma zedoaria ROSCOE (Zingiberaceae). Principal sesquiterpenes, furanodiene, germacrone, curdione, neocurdione, curcumenol, isocurcumenol, aerugidiol, zedoarondiol, and curcumenone and curcumin were found to show potent protective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver injury in mice. Plausible action mechanisms for their hepatoprotective activity were clarified on the basis of the inhibitory effect on D-GalN-induced cytotoxicity in primary cultured rat hepatocytes, LPS-induced NO production in cultured mouse peritoneal macrophages, and D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced liver injury in mice.
|
Inhibition of P-gp was determined using rhodamine-assay in human CaCo-2 cells
|
None
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Compound evaluated for inhibition of rat paw swelling after ip administration at 0.30 mg/kg in acute phase
|
Rattus norvegicus
|
32.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and biological activity of a series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates as antineoplastic and antiarthritic agents.
Year : 1999
Volume : 9
Issue : 1
First Page : 75
Last Page : 78
Authors : Gossett LS, Habeck LL, Shackelford KA, Mendelsohn LG, Gates SB, Worzalla JF, Self TD, Theobald KS, Andis SL, Schultz RM, Shih C.
Abstract : A new series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates 1-3 were synthesized through an efficient conversion of 2-pivaloyl-4-oxo-6-ethynylpyrido[2,3-d]pyrimidine 5 to the corresponding 4-amino analog 7 via the activated 1,2,4-triazole intermediate 6. Compound 7 was used as the key intermediate for the preparation of the final products. The detailed biological evaluation of these compounds both as antineoplastic and antiarthritic agents will be discussed.
|
Compound evaluated for inhibition of rat paw swelling after ip administration at 0.30 mg/kg in delayed phase
|
Rattus norvegicus
|
36.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and biological activity of a series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates as antineoplastic and antiarthritic agents.
Year : 1999
Volume : 9
Issue : 1
First Page : 75
Last Page : 78
Authors : Gossett LS, Habeck LL, Shackelford KA, Mendelsohn LG, Gates SB, Worzalla JF, Self TD, Theobald KS, Andis SL, Schultz RM, Shih C.
Abstract : A new series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates 1-3 were synthesized through an efficient conversion of 2-pivaloyl-4-oxo-6-ethynylpyrido[2,3-d]pyrimidine 5 to the corresponding 4-amino analog 7 via the activated 1,2,4-triazole intermediate 6. Compound 7 was used as the key intermediate for the preparation of the final products. The detailed biological evaluation of these compounds both as antineoplastic and antiarthritic agents will be discussed.
|
Compound was evaluated for its inhibitory effects on passive cutaneous anaphylaxis in rats at a dose of 1 (mg / site).
|
Rattus norvegicus
|
6.99
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and topical antiinflammatory and antiallergic activities of antioxidant o-aminophenol derivatives.
Year : 1994
Volume : 37
Issue : 13
First Page : 1977
Last Page : 1982
Authors : Sugiyama N, Akahoshi F, Kuwahara S, Kajii M, Sakaue Y, Yakumaru H, Sugiura M, Fukaya C.
Abstract : In order to develop novel compounds for topical use possessing antiallergic as well as antiinflammatory activities, a series of o-aminophenol derivatives bearing H1-antihistaminic structures were synthesized and their effects were investigated on lipid peroxidation in rat brain homogenates, antiinflammatory effection arachidonic acid- and 12-O-tetradecanoylphorbol-13- acetate-induced mouse ear edema and antiallergic effect on 48-h homologous passive cutaneous anaphylaxis in rats. Furthermore, the effects of these compounds on delayed-type hypersensitivity reaction in mice were examined. Several N-monosubstituted amino-4-methylphenols were found to exert potent inhibitory activities in all of these assays. Of these compounds, 4m was chosen for further development as AD0261.
|
Compound was evaluated for its inhibitory effects on passive cutaneous anaphylaxis in rats at a dose of 2.5 (mg / site).
|
Rattus norvegicus
|
-16.4
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and topical antiinflammatory and antiallergic activities of antioxidant o-aminophenol derivatives.
Year : 1994
Volume : 37
Issue : 13
First Page : 1977
Last Page : 1982
Authors : Sugiyama N, Akahoshi F, Kuwahara S, Kajii M, Sakaue Y, Yakumaru H, Sugiura M, Fukaya C.
Abstract : In order to develop novel compounds for topical use possessing antiallergic as well as antiinflammatory activities, a series of o-aminophenol derivatives bearing H1-antihistaminic structures were synthesized and their effects were investigated on lipid peroxidation in rat brain homogenates, antiinflammatory effection arachidonic acid- and 12-O-tetradecanoylphorbol-13- acetate-induced mouse ear edema and antiallergic effect on 48-h homologous passive cutaneous anaphylaxis in rats. Furthermore, the effects of these compounds on delayed-type hypersensitivity reaction in mice were examined. Several N-monosubstituted amino-4-methylphenols were found to exert potent inhibitory activities in all of these assays. Of these compounds, 4m was chosen for further development as AD0261.
|
50 percent inhibitory concentration of compound to inhibit nitric oxide production induced by IFN-gamma in mouse macrophages
|
Mus musculus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel synthetic oleanane and ursane triterpenoids with various enone functionalities in ring A as inhibitors of nitric oxide production in mouse macrophages.
Year : 2000
Volume : 43
Issue : 9
First Page : 1866
Last Page : 1877
Authors : Honda T, Gribble GW, Suh N, Finlay HJ, Rounds BV, Bore L, Favaloro FG, Wang Y, Sporn MB.
Abstract : We initially randomly synthesized about 60 oleanane and ursane triterpenoids as potential anti-inflammatory and cancer chemopreventive agents. Preliminary screening of these derivatives for inhibition of production of nitric oxide induced by interferon-gamma in mouse macrophages revealed that 3-oxooleana-1, 12-dien-28-oic acid (B-15) showed significant activity (IC(50) = 5.6 microM). On the basis of the structure of B-15, 19 novel olean- and urs-12-ene triterpenoids with a 1-en-3-one functionality having a substituent at C-2 in ring A have been designed and synthesized. Among them, 3-oxooleana-1,12-diene derivatives with carboxyl, methoxycarbonyl, and nitrile groups at C-2 showed higher activity than the lead compound B-15. In particular, 2-carboxy-3-oxooleana-1, 12-dien-28-oic acid (3) had the highest activity (IC(50) = 0.07 microM) in this group of triterpenoids. The potency of 3 was similar to that of hydrocortisone (IC(50) = 0.01 microM), although 3 does not act through the glucocorticoid receptor. Interesting structure-activity relationships of these novel synthetic triterpenoids are also discussed.
|
Inhibition of nitric oxide (NO) production induced by interferon-gamma (IFN-gamma) in mouse macrophages
|
Mus musculus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthetic oleanane and ursane triterpenoids with modified rings A and C: a series of highly active inhibitors of nitric oxide production in mouse macrophages.
Year : 2000
Volume : 43
Issue : 22
First Page : 4233
Last Page : 4246
Authors : Honda T, Rounds BV, Bore L, Finlay HJ, Favaloro FG, Suh N, Wang Y, Sporn MB, Gribble GW.
Abstract : We have designed and synthesized 16 new olean- and urs-1-en-3-one triterpenoids with various modified rings C as potential antiinflammatory and cancer chemopreventive agents and evaluated their inhibitory activities against production of nitric oxide induced by interferon-gamma in mouse macrophages. This investigation revealed that 9(11)-en-12-one and 12-en-11-one functionalities in ring C increase the potency by about 2-10 times compared with the original 12-ene. Subsequently, we have designed and synthesized novel olean- and urs-1-en-3-one derivatives with nitrile and carboxyl groups at C-2 in ring A and with 9(11)-en-12-one and 12-en-11-one functionalities in ring C. Among them, we have found that methyl 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oate (25), 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) (26), and methyl 2-carboxy-3,12-dioxooleana-1,9(11)-dien-28-oate (29) have extremely high potency (IC(50) = 0.1 nM level). Their potency is similar to that of dexamethasone although they do not act through the glucocorticoid receptor. Overall, the combination of modified rings A and C increases the potency by about 10 000 times compared with the lead compound, 3-oxooleana-1,12-dien-28-oic acid (8) (IC(50) = 1 microM level). The selected oleanane triterpenoid, CDDO (26), was found to be a potent, multifunctional agent in various in vitro assays and to show antiinflammatory activity against thioglycollate-interferon-gamma-induced mouse peritonitis.
|
Inhibitory activity against nitric oxide production induced by interferon-gamma (IFN-gamma) in mouse macrophages
|
Mus musculus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of tricyclic compounds with enone functionalities in rings A and C: a novel class of highly active inhibitors of nitric oxide production in mouse macrophages.
Year : 2002
Volume : 45
Issue : 22
First Page : 4801
Last Page : 4805
Authors : Favaloro FG, Honda T, Honda Y, Gribble GW, Suh N, Risingsong R, Sporn MB.
Abstract : Novel tricyclic compounds with enone functionalities in rings A and C, which were designed on the basis of the structure of a synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid, have been synthesized. Among them, 10 shows high inhibitory activity (IC(50) = 1 nM level) against production of nitric oxide induced by interferon-gamma in mouse macrophages and is orally active at 15 mg/kg (once) in a preliminary in vivo study using mouse peritoneal inflammation induced by thioglycollate and interferon-gamma.
|
Percent inhibition of nitric oxide production induced by IFN-uM concentration
|
Mus musculus
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : Novel synthetic oleanane and ursane triterpenoids with various enone functionalities in ring A as inhibitors of nitric oxide production in mouse macrophages.
Year : 2000
Volume : 43
Issue : 9
First Page : 1866
Last Page : 1877
Authors : Honda T, Gribble GW, Suh N, Finlay HJ, Rounds BV, Bore L, Favaloro FG, Wang Y, Sporn MB.
Abstract : We initially randomly synthesized about 60 oleanane and ursane triterpenoids as potential anti-inflammatory and cancer chemopreventive agents. Preliminary screening of these derivatives for inhibition of production of nitric oxide induced by interferon-gamma in mouse macrophages revealed that 3-oxooleana-1, 12-dien-28-oic acid (B-15) showed significant activity (IC(50) = 5.6 microM). On the basis of the structure of B-15, 19 novel olean- and urs-12-ene triterpenoids with a 1-en-3-one functionality having a substituent at C-2 in ring A have been designed and synthesized. Among them, 3-oxooleana-1,12-diene derivatives with carboxyl, methoxycarbonyl, and nitrile groups at C-2 showed higher activity than the lead compound B-15. In particular, 2-carboxy-3-oxooleana-1, 12-dien-28-oic acid (3) had the highest activity (IC(50) = 0.07 microM) in this group of triterpenoids. The potency of 3 was similar to that of hydrocortisone (IC(50) = 0.01 microM), although 3 does not act through the glucocorticoid receptor. Interesting structure-activity relationships of these novel synthetic triterpenoids are also discussed.
|
Inhibition of peribronchial eosinophilia in BALB/c mouse at 100 mg/kg, po relative to control
|
Mus musculus
|
94.0
%
|
|
Journal : J. Med. Chem.
Title : Novel selective orally active CRTH2 antagonists for allergic inflammation developed from in silico derived hits.
Year : 2006
Volume : 49
Issue : 23
First Page : 6638
Last Page : 6641
Authors : Ulven T, Receveur JM, Grimstrup M, Rist Ø, Frimurer TM, Gerlach LO, Mathiesen JM, Kostenis E, Uller L, Högberg T.
Abstract : Hits from an in silico derived focused library for CRTH2 were transformed into highly selective antagonists with favorable ADME properties. Oral administration of 4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid (19) inhibited peribronchial eosinophilia and mucus cell hyperplasia in a mouse model of allergic asthma, supporting the therapeutic potential of this novel compound class. In addition, this selective pharmacological tool compound provides further evidence for CRTH2 as a relevant therapeutic target for treatment of Th2- and eosinophil-related inflammation.
|
Inhibition of D-galactosamine/LPS-induced liver injury in ddY mouse assessed as serum GOT level at 10 mg/kg, po
|
Mus musculus
|
94.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Protective effects of amide constituents from the fruit of Piper chaba on D-galactosamine/TNF-alpha-induced cell death in mouse hepatocytes.
Year : 2008
Volume : 18
Issue : 6
First Page : 2038
Last Page : 2042
Authors : Matsuda H, Ninomiya K, Morikawa T, Yasuda D, Yamaguchi I, Yoshikawa M.
Abstract : The methanolic extract from the fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the ethyl acetate-soluble fraction, a new amide constituent named piperchabamide E together with twenty known amide constituents (e.g., piperine, piperchabamides A-D, and piperanine) and two aromatic constituents were isolated as the hepatoprotective constituents. With regard to structure-activity relationships, the amide moiety and the 1,9-decadiene structure between the benzene ring and amide moiety were suggested to be important for strong inhibition of D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes. Furthermore, a principal amide constituent, piperine, dose-dependently inhibited increase in serum GPT and GOT levels at doses of 2.5-10 mg/kg (p.o.) in D-GalN/LPS-treated mice, and this inhibitory effect was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.
|
Inhibition of D-galactosamine/LPS-induced liver injury in ddY mouse assessed as serum GPT level at 10 mg/kg, po
|
Mus musculus
|
97.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Protective effects of amide constituents from the fruit of Piper chaba on D-galactosamine/TNF-alpha-induced cell death in mouse hepatocytes.
Year : 2008
Volume : 18
Issue : 6
First Page : 2038
Last Page : 2042
Authors : Matsuda H, Ninomiya K, Morikawa T, Yasuda D, Yamaguchi I, Yoshikawa M.
Abstract : The methanolic extract from the fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the ethyl acetate-soluble fraction, a new amide constituent named piperchabamide E together with twenty known amide constituents (e.g., piperine, piperchabamides A-D, and piperanine) and two aromatic constituents were isolated as the hepatoprotective constituents. With regard to structure-activity relationships, the amide moiety and the 1,9-decadiene structure between the benzene ring and amide moiety were suggested to be important for strong inhibition of D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes. Furthermore, a principal amide constituent, piperine, dose-dependently inhibited increase in serum GPT and GOT levels at doses of 2.5-10 mg/kg (p.o.) in D-GalN/LPS-treated mice, and this inhibitory effect was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.
|
Inhibition of D-galactosamine/LPS-induced TNFalpha level in ddY mouse serum at 10 mg/kg, po by ELISA
|
Mus musculus
|
92.1
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Protective effects of amide constituents from the fruit of Piper chaba on D-galactosamine/TNF-alpha-induced cell death in mouse hepatocytes.
Year : 2008
Volume : 18
Issue : 6
First Page : 2038
Last Page : 2042
Authors : Matsuda H, Ninomiya K, Morikawa T, Yasuda D, Yamaguchi I, Yoshikawa M.
Abstract : The methanolic extract from the fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the ethyl acetate-soluble fraction, a new amide constituent named piperchabamide E together with twenty known amide constituents (e.g., piperine, piperchabamides A-D, and piperanine) and two aromatic constituents were isolated as the hepatoprotective constituents. With regard to structure-activity relationships, the amide moiety and the 1,9-decadiene structure between the benzene ring and amide moiety were suggested to be important for strong inhibition of D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes. Furthermore, a principal amide constituent, piperine, dose-dependently inhibited increase in serum GPT and GOT levels at doses of 2.5-10 mg/kg (p.o.) in D-GalN/LPS-treated mice, and this inhibitory effect was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.
|
Displacement of [3H]5alpha dihydrotestosterone from human sex hormone binding globulin
|
Homo sapiens
|
630.96
nM
|
|
Journal : J. Med. Chem.
Title : An updated steroid benchmark set and its application in the discovery of novel nanomolar ligands of sex hormone-binding globulin.
Year : 2008
Volume : 51
Issue : 7
First Page : 2047
Last Page : 2056
Authors : Cherkasov A, Ban F, Santos-Filho O, Thorsteinson N, Fallahi M, Hammond GL.
Abstract : A benchmark data set of steroids with known affinity for sex hormone-binding globulin (SHBG) has been widely used to validate popular molecular field-based QSAR techniques. We have expanded the data set by adding a number of nonsteroidal SHBG ligands identified both from the literature and in our previous experimental studies. This updated molecular set has been used herein to develop 4D QSAR models based on "inductive" descriptors and to gain insight into the molecular basis of protein-ligand interactions. Molecular alignment was generated by means of docking active compounds into the active site of the SHBG. Surprisingly, the alignment of the benchmark steroids contradicted the classical ligand-based alignment utilized in previous CoMFA and CoMSIA models yet afforded models with higher statistical significance and predictive power. The resulting QSAR models combined with CoMFA and CoMSiA models as well as structure-based virtual screening allowed discovering several low-micromolar to nanomolar nonsteroidal inhibitors for human SHBG.
|
Hepatoprotective activity against D-galactosamine/LPS-induced liver injury in ddY mouse assessed as inhibition of serum alanine transaminase level at 20 mg/kg, ip administered 1 hr before D-galactosamine/LPS challenge by Reitman-Frankel method
|
Mus musculus
|
99.0
%
|
|
Journal : J. Nat. Prod.
Title : Structures of new dammarane-type Triterpene Saponins from the flower buds of Panax notoginseng and hepatoprotective effects of principal Ginseng Saponins.
Year : 2003
Volume : 66
Issue : 7
First Page : 922
Last Page : 927
Authors : Yoshikawa M, Morikawa T, Kashima Y, Ninomiya K, Matsuda H.
Abstract : The saponin fraction from the flower buds of Panax notoginseng exhibited protective effect on liver injury induced by d-galactosamine and lipopolysaccharide. From the saponin fraction with hepatoprotective effect, five new dammarane-type triterpene saponins, notoginsenosides-O (1), -P (2), -Q (3), -S (4), and -T (5), were isolated together with nine known protopanaxadiol oligoglycosides. The structures of the new saponins were elucidated on the basis of chemical and physicochemical evidence. The principal dammarane-type triterpene saponins from the roots and flower buds of Panax notoginseng were found to show potent hepatoprotective effects.
|
Hepatoprotective activity against D-galactosamine/LPS-induced liver injury in ddY mouse assessed as inhibition of serum aspartate transaminase level at 20 mg/kg, ip administered 1 hr before D-galactosamine/LPS challenge by Reitman-Frankel method
|
Mus musculus
|
97.0
%
|
|
Journal : J. Nat. Prod.
Title : Structures of new dammarane-type Triterpene Saponins from the flower buds of Panax notoginseng and hepatoprotective effects of principal Ginseng Saponins.
Year : 2003
Volume : 66
Issue : 7
First Page : 922
Last Page : 927
Authors : Yoshikawa M, Morikawa T, Kashima Y, Ninomiya K, Matsuda H.
Abstract : The saponin fraction from the flower buds of Panax notoginseng exhibited protective effect on liver injury induced by d-galactosamine and lipopolysaccharide. From the saponin fraction with hepatoprotective effect, five new dammarane-type triterpene saponins, notoginsenosides-O (1), -P (2), -Q (3), -S (4), and -T (5), were isolated together with nine known protopanaxadiol oligoglycosides. The structures of the new saponins were elucidated on the basis of chemical and physicochemical evidence. The principal dammarane-type triterpene saponins from the roots and flower buds of Panax notoginseng were found to show potent hepatoprotective effects.
|
Hepatoprotective activity in ddY mouse assessed as inhibition of D-galactosamine/LPS-induced liver injury by measuring serum aspartate aminotransferase activity at 10 mg/kg, po dosed 1 hr before D-GalN/LPS challenge relative to untreated control
|
Mus musculus
|
94.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Hepatoprotective amide constituents from the fruit of Piper chaba: Structural requirements, mode of action, and new amides.
Year : 2009
Volume : 17
Issue : 20
First Page : 7313
Last Page : 7323
Authors : Matsuda H, Ninomiya K, Morikawa T, Yasuda D, Yamaguchi I, Yoshikawa M.
Abstract : The 80% aqueous acetone extract from the fruit of Piper chaba (Piperaceae) was found to have hepatoprotective effects on D-galactosamine (D-GalN)/lipopolysaccharide-induced liver injury in mice. From the ethyl acetate-soluble fraction, three new amides, piperchabamides E, G, and H, 33 amides, and four aromatic constituents were isolated. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes, and the following structural requirements were suggested: (i) the amide moiety is essential for potent activity; and (ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effects at doses of 5 and 10 mg/kg, po and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.
|
Hepatoprotective activity in ddY mouse assessed as inhibition of D-galactosamine/LPS-induced liver injury by measuring serum alanine aminotransferase activity at 10 mg/kg, po dosed 1 hr before D-GalN/LPS challenge relative to untreated control
|
Mus musculus
|
97.7
%
|
|
Journal : Bioorg. Med. Chem.
Title : Hepatoprotective amide constituents from the fruit of Piper chaba: Structural requirements, mode of action, and new amides.
Year : 2009
Volume : 17
Issue : 20
First Page : 7313
Last Page : 7323
Authors : Matsuda H, Ninomiya K, Morikawa T, Yasuda D, Yamaguchi I, Yoshikawa M.
Abstract : The 80% aqueous acetone extract from the fruit of Piper chaba (Piperaceae) was found to have hepatoprotective effects on D-galactosamine (D-GalN)/lipopolysaccharide-induced liver injury in mice. From the ethyl acetate-soluble fraction, three new amides, piperchabamides E, G, and H, 33 amides, and four aromatic constituents were isolated. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes, and the following structural requirements were suggested: (i) the amide moiety is essential for potent activity; and (ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effects at doses of 5 and 10 mg/kg, po and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.
|
Hepatoprotective activity in ddY mouse assessed as inhibition of D-galactosamine/LPS-induced increase in serum TNFalpha level at 20 mg/kg, po dosed 1 hr before D-GalN/LPS challenge relative to untreated control
|
Mus musculus
|
92.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Hepatoprotective amide constituents from the fruit of Piper chaba: Structural requirements, mode of action, and new amides.
Year : 2009
Volume : 17
Issue : 20
First Page : 7313
Last Page : 7323
Authors : Matsuda H, Ninomiya K, Morikawa T, Yasuda D, Yamaguchi I, Yoshikawa M.
Abstract : The 80% aqueous acetone extract from the fruit of Piper chaba (Piperaceae) was found to have hepatoprotective effects on D-galactosamine (D-GalN)/lipopolysaccharide-induced liver injury in mice. From the ethyl acetate-soluble fraction, three new amides, piperchabamides E, G, and H, 33 amides, and four aromatic constituents were isolated. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes, and the following structural requirements were suggested: (i) the amide moiety is essential for potent activity; and (ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effects at doses of 5 and 10 mg/kg, po and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.
|
Hepatoprotective activity against D-galactosamine/lipopolysaccharide-induced liver injury in ddY mouse assessed as inhibition of increase in sAST level at 10 mg/kg, po administered 1 hr before D-GalN/LPS challenge measured after 10 hrs
|
Mus musculus
|
94.2
%
|
|
Journal : Bioorg. Med. Chem.
Title : Acylated phenylethanoid oligoglycosides with hepatoprotective activity from the desert plant Cistanche tubulosa.
Year : 2010
Volume : 18
Issue : 5
First Page : 1882
Last Page : 1890
Authors : Morikawa T, Pan Y, Ninomiya K, Imura K, Matsuda H, Yoshikawa M, Yuan D, Muraoka O.
Abstract : The methanolic extract from fresh stems of Cistanche tubulosa (Orobanchaceae) was found to show hepatoprotective effects against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the extract, three new phenylethanoid oligoglycosides, kankanosides H(1) (1), H(2) (2), and I (3), were isolated together with 16 phenylethanoid glycosides (4-19) and two acylated oligosugars (20, 21). The structures of 1-3 were determined on the basis of spectroscopic properties as well as of chemical evidence. Among the isolates, echinacoside (4, IC(50)=10.2 microM), acteoside (5, 4.6 microM), isoacteoside (6, 5.3 microM), 2'-acetylacteoside (8, 4.8 microM), and tubuloside A (10, 8.6 microM) inhibited D-GalN-induced death of hepatocytes. These five isolates, 4 (31.1 microM), 5 (17.8 microM), 6 (22.7 microM), 8 (25.7 microM), and 10 (23.2 microM), and cistantubuloside B(1) (11, 21.4 microM) also reduced TNF-alpha-induced cytotoxicity in L929 cells. Moreover, principal constituents (4-6) exhibited in vivo hepatoprotective effects at doses of 25-100mg/kg, po.
|
Hepatoprotective activity against D-galactosamine/lipopolysaccharide-induced liver injury in ddY mouse assessed as inhibition of increase in sALT level at 10 mg/kg, po administered 1 hr before D-GalN/LPS challenge measured after 10 hrs
|
Mus musculus
|
97.7
%
|
|
Journal : Bioorg. Med. Chem.
Title : Acylated phenylethanoid oligoglycosides with hepatoprotective activity from the desert plant Cistanche tubulosa.
Year : 2010
Volume : 18
Issue : 5
First Page : 1882
Last Page : 1890
Authors : Morikawa T, Pan Y, Ninomiya K, Imura K, Matsuda H, Yoshikawa M, Yuan D, Muraoka O.
Abstract : The methanolic extract from fresh stems of Cistanche tubulosa (Orobanchaceae) was found to show hepatoprotective effects against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the extract, three new phenylethanoid oligoglycosides, kankanosides H(1) (1), H(2) (2), and I (3), were isolated together with 16 phenylethanoid glycosides (4-19) and two acylated oligosugars (20, 21). The structures of 1-3 were determined on the basis of spectroscopic properties as well as of chemical evidence. Among the isolates, echinacoside (4, IC(50)=10.2 microM), acteoside (5, 4.6 microM), isoacteoside (6, 5.3 microM), 2'-acetylacteoside (8, 4.8 microM), and tubuloside A (10, 8.6 microM) inhibited D-GalN-induced death of hepatocytes. These five isolates, 4 (31.1 microM), 5 (17.8 microM), 6 (22.7 microM), 8 (25.7 microM), and 10 (23.2 microM), and cistantubuloside B(1) (11, 21.4 microM) also reduced TNF-alpha-induced cytotoxicity in L929 cells. Moreover, principal constituents (4-6) exhibited in vivo hepatoprotective effects at doses of 25-100mg/kg, po.
|
Inhibition of human 17beta-HSD7 expressed in HEK293 cells assessed as inhibition of reduction of [14C]estrone into [14C]estradiol at 3 uM after 7 hrs
|
Homo sapiens
|
10.3
%
|
|
Journal : J. Med. Chem.
Title : Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.
Year : 2009
Volume : 52
Issue : 23
First Page : 7488
Last Page : 7502
Authors : Bellavance E, Luu-The V, Poirier D.
Abstract : 17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.
|
Antiinflammatory activity in CD-1 mouse Macrophage assessed as inhibition of IFN-gamma induced NO production after 48 hrs by Griess reaction
|
Mus musculus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic compounds containing nonenolizable cyano enones. A novel class of highly potent anti-inflammatory and cytoprotective agents.
Year : 2011
Volume : 54
Issue : 6
First Page : 1762
Last Page : 1778
Authors : Honda T, Yoshizawa H, Sundararajan C, David E, Lajoie MJ, Favaloro FG, Janosik T, Su X, Honda Y, Roebuck BD, Gribble GW.
Abstract : Forty-four novel tricycles containing nonenolizable cyano enones (TCEs) were designed and synthesized on the basis of a semisynthetic pentacyclic triterpenoid, bardoxolone methyl, which is currently being developed in phase II clinical trials for the treatment of severe chronic kidney disease in diabetic patients. Most of the TCEs having two different kinds of nonenolizable cyano enones in rings A and C are highly potent suppressors of induction of inducible nitric oxide synthase stimulated with interferon-γ and are highly potent inducers of the cytoprotective enzymes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Among these compounds, (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile ((±)-31) is the most potent in these bioassays in our pool of drug candidates including semisynthetic triterpenoids and synthetic tricycles. These facts strongly suggest that an essential factor for potency is not a triterpenoid skeleton but the cyano enone functionality. Notably, TCE 31 reduces hepatic tumorigenesis induced with aflatoxin in rats. Further preclinical studies and detailed mechanism studies on 31 are in progress.
|
Antiinflammatory activity in mouse RAW264.7 cells assessed as inhibition of IFN-gamma induced NO production after 24 hrs by Griess reaction
|
Mus musculus
|
61.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic compounds containing nonenolizable cyano enones. A novel class of highly potent anti-inflammatory and cytoprotective agents.
Year : 2011
Volume : 54
Issue : 6
First Page : 1762
Last Page : 1778
Authors : Honda T, Yoshizawa H, Sundararajan C, David E, Lajoie MJ, Favaloro FG, Janosik T, Su X, Honda Y, Roebuck BD, Gribble GW.
Abstract : Forty-four novel tricycles containing nonenolizable cyano enones (TCEs) were designed and synthesized on the basis of a semisynthetic pentacyclic triterpenoid, bardoxolone methyl, which is currently being developed in phase II clinical trials for the treatment of severe chronic kidney disease in diabetic patients. Most of the TCEs having two different kinds of nonenolizable cyano enones in rings A and C are highly potent suppressors of induction of inducible nitric oxide synthase stimulated with interferon-γ and are highly potent inducers of the cytoprotective enzymes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Among these compounds, (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile ((±)-31) is the most potent in these bioassays in our pool of drug candidates including semisynthetic triterpenoids and synthetic tricycles. These facts strongly suggest that an essential factor for potency is not a triterpenoid skeleton but the cyano enone functionality. Notably, TCE 31 reduces hepatic tumorigenesis induced with aflatoxin in rats. Further preclinical studies and detailed mechanism studies on 31 are in progress.
|
DRUGMATRIX: Glucocorticoid radioligand binding (ligand: [3H] Dexamethasone)
|
None
|
26.0
nM
|
|
DRUGMATRIX: Glucocorticoid radioligand binding (ligand: [3H] Dexamethasone)
|
None
|
12.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
TP_TRANSPORTER: inhibition of Digoxin transepithelial transport (basal to apical)(Digoxin: 5 uM, Cortisol: 100 uM) in Caco-2 cells
|
None
|
56.0
%
|
|
Journal : Pharm. Res.
Title : Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein.
Year : 1999
Volume : 16
Issue : 1
First Page : 408
Last Page : 414
Authors : Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, Roden MM, Belas F, Chaudhary AK, Roden DM, Wood AJ, Wilkinson GR.
Abstract : PURPOSE: CYP3A and P-gp both function to reduce the intracellular concentration of drug substrates, one by metabolism and the other by transmembrane efflux. Moreover, it has been serendipitously noted that the two proteins have many common substrates and inhibitors. In order to test this notion more fully, systematic studies were undertaken to determine the P-gp-mediated transport and inhibitory characteristics of prototypical CYP substrates. METHODS: L-MDR1, LLC-PK1, and Caco-2 cells were used to evaluate established CYP substrates as potential P-gp substrates and inhibitors in vitro, and mdr1a deficient mice were used to assess the in vivo relevance of P-gp-mediated transport. RESULTS: Some (terfenadine, erythromycin and lovastatin) but not all (nifedipine and midazolam) CYP3A substrates were found to be P-gp substrates. Except for debrisoquine, none of the prototypical substrates of other common human CYP isoforms were transported by P-gp. Studies in mdr1a disrupted mice confirmed that erythromycin was a P-gp substrate but the CYP3A-inhibitor ketoconazole was not. In addition, CYP3A substrates and inhibitors varied widely in their ability to inhibit the P-gp-mediated transport of digoxin. CONCLUSIONS: These results indicate that the overlap in substrate specificities of CYP3A and P-gp appears to be fortuitous rather than indicative of a more fundamental relationship.
|
Antiinflammatory activity in CD1 mouse ear dermatitis model assessed as inhibition of Croton oil-induced ear edema at 0.10 umol administered topically per cm'2 of ear measured after induction of dermatitis relative to untreated control
|
Mus musculus
|
77.0
%
|
|
Journal : J. Nat. Prod.
Title : Lignan derivatives from Krameria lappacea roots inhibit acute inflammation in vivo and pro-inflammatory mediators in vitro.
Year : 2011
Volume : 74
Issue : 8
First Page : 1779
Last Page : 1786
Authors : Baumgartner L, Sosa S, Atanasov AG, Bodensieck A, Fakhrudin N, Bauer J, Favero GD, Ponti C, Heiss EH, Schwaiger S, Ladurner A, Widowitz U, Loggia RD, Rollinger JM, Werz O, Bauer R, Dirsch VM, Tubaro A, Stuppner H.
Abstract : The roots of Krameria lappacea are used traditionally against oropharyngeal inflammation. So far, the astringent and antimicrobial properties of its proanthocyanidin constituents are considered to account for the anti-inflammatory effect. The aim of the present study was to characterize pharmacologically a lipophilic extract of K. lappacea roots and several isolated lignan derivatives (1-11) in terms of their putative anti-inflammatory activity. The dichloromethane extract (ID₅₀ 77 μg/cm²) as well compounds 1-11 (ID₅₀ 0.31-0.60 μmol/cm²) exhibited topical antiedematous properties comparable to those of indomethacin (ID₅₀ 0.29 μmol/cm²) in a mouse ear in vivo model. Two of the most potent compounds, 2-(2-hydroxy-4-methoxyphenyl)-5-(3-hydroxypropyl)benzofuran (5) and (+)-conocarpan (7), were studied regarding their time-dependent edema development and leukocyte infiltration up to 48 h after croton oil-induced dermatitis induction, and they showed activity profiles similar to that of hydrocortisone. In vitro studies of the isolated lignan derivatives demonstrated the inhibition of NF-κB, cyclooxygenase-1 and -2, 5-lipoxygenase, and microsomal prostaglandin E₂ synthase-1 as well as antioxidant properties, as mechanisms possibly contributing to the observed in vivo effects. The present findings not only support the ethnopharmacological use of K. lappacea roots but also reveal that the isolated lignan derivatives contribute strongly to the anti-inflammatory activity of this herbal drug.
|
Antiinflammatory activity in CD1 mouse ear dermatitis model assessed as inhibition of Croton oil-induced ear edema at 0.04 umol administered topically per cm'2 of ear measured 6 hrs after induction of dermatitis relative to untreated control
|
Mus musculus
|
79.0
%
|
|
Journal : J. Nat. Prod.
Title : Lignan derivatives from Krameria lappacea roots inhibit acute inflammation in vivo and pro-inflammatory mediators in vitro.
Year : 2011
Volume : 74
Issue : 8
First Page : 1779
Last Page : 1786
Authors : Baumgartner L, Sosa S, Atanasov AG, Bodensieck A, Fakhrudin N, Bauer J, Favero GD, Ponti C, Heiss EH, Schwaiger S, Ladurner A, Widowitz U, Loggia RD, Rollinger JM, Werz O, Bauer R, Dirsch VM, Tubaro A, Stuppner H.
Abstract : The roots of Krameria lappacea are used traditionally against oropharyngeal inflammation. So far, the astringent and antimicrobial properties of its proanthocyanidin constituents are considered to account for the anti-inflammatory effect. The aim of the present study was to characterize pharmacologically a lipophilic extract of K. lappacea roots and several isolated lignan derivatives (1-11) in terms of their putative anti-inflammatory activity. The dichloromethane extract (ID₅₀ 77 μg/cm²) as well compounds 1-11 (ID₅₀ 0.31-0.60 μmol/cm²) exhibited topical antiedematous properties comparable to those of indomethacin (ID₅₀ 0.29 μmol/cm²) in a mouse ear in vivo model. Two of the most potent compounds, 2-(2-hydroxy-4-methoxyphenyl)-5-(3-hydroxypropyl)benzofuran (5) and (+)-conocarpan (7), were studied regarding their time-dependent edema development and leukocyte infiltration up to 48 h after croton oil-induced dermatitis induction, and they showed activity profiles similar to that of hydrocortisone. In vitro studies of the isolated lignan derivatives demonstrated the inhibition of NF-κB, cyclooxygenase-1 and -2, 5-lipoxygenase, and microsomal prostaglandin E₂ synthase-1 as well as antioxidant properties, as mechanisms possibly contributing to the observed in vivo effects. The present findings not only support the ethnopharmacological use of K. lappacea roots but also reveal that the isolated lignan derivatives contribute strongly to the anti-inflammatory activity of this herbal drug.
|
Antiinflammatory activity in CD1 mouse ear dermatitis model assessed as inhibition of Croton oil-induced ear edema at 0.04 umol administered topically per cm'2 of ear measured 12 hrs after induction of dermatitis relative to untreated control
|
Mus musculus
|
60.0
%
|
|
Journal : J. Nat. Prod.
Title : Lignan derivatives from Krameria lappacea roots inhibit acute inflammation in vivo and pro-inflammatory mediators in vitro.
Year : 2011
Volume : 74
Issue : 8
First Page : 1779
Last Page : 1786
Authors : Baumgartner L, Sosa S, Atanasov AG, Bodensieck A, Fakhrudin N, Bauer J, Favero GD, Ponti C, Heiss EH, Schwaiger S, Ladurner A, Widowitz U, Loggia RD, Rollinger JM, Werz O, Bauer R, Dirsch VM, Tubaro A, Stuppner H.
Abstract : The roots of Krameria lappacea are used traditionally against oropharyngeal inflammation. So far, the astringent and antimicrobial properties of its proanthocyanidin constituents are considered to account for the anti-inflammatory effect. The aim of the present study was to characterize pharmacologically a lipophilic extract of K. lappacea roots and several isolated lignan derivatives (1-11) in terms of their putative anti-inflammatory activity. The dichloromethane extract (ID₅₀ 77 μg/cm²) as well compounds 1-11 (ID₅₀ 0.31-0.60 μmol/cm²) exhibited topical antiedematous properties comparable to those of indomethacin (ID₅₀ 0.29 μmol/cm²) in a mouse ear in vivo model. Two of the most potent compounds, 2-(2-hydroxy-4-methoxyphenyl)-5-(3-hydroxypropyl)benzofuran (5) and (+)-conocarpan (7), were studied regarding their time-dependent edema development and leukocyte infiltration up to 48 h after croton oil-induced dermatitis induction, and they showed activity profiles similar to that of hydrocortisone. In vitro studies of the isolated lignan derivatives demonstrated the inhibition of NF-κB, cyclooxygenase-1 and -2, 5-lipoxygenase, and microsomal prostaglandin E₂ synthase-1 as well as antioxidant properties, as mechanisms possibly contributing to the observed in vivo effects. The present findings not only support the ethnopharmacological use of K. lappacea roots but also reveal that the isolated lignan derivatives contribute strongly to the anti-inflammatory activity of this herbal drug.
|
Antiinflammatory activity in CD1 mouse ear dermatitis model assessed as reduction in AUC of of Croton oil-induced ear edema response at 0.04 umol administered topically per cm'2 of ear measured 48 hrs after induction of dermatitis relative to untreated control
|
Mus musculus
|
69.0
%
|
|
Journal : J. Nat. Prod.
Title : Lignan derivatives from Krameria lappacea roots inhibit acute inflammation in vivo and pro-inflammatory mediators in vitro.
Year : 2011
Volume : 74
Issue : 8
First Page : 1779
Last Page : 1786
Authors : Baumgartner L, Sosa S, Atanasov AG, Bodensieck A, Fakhrudin N, Bauer J, Favero GD, Ponti C, Heiss EH, Schwaiger S, Ladurner A, Widowitz U, Loggia RD, Rollinger JM, Werz O, Bauer R, Dirsch VM, Tubaro A, Stuppner H.
Abstract : The roots of Krameria lappacea are used traditionally against oropharyngeal inflammation. So far, the astringent and antimicrobial properties of its proanthocyanidin constituents are considered to account for the anti-inflammatory effect. The aim of the present study was to characterize pharmacologically a lipophilic extract of K. lappacea roots and several isolated lignan derivatives (1-11) in terms of their putative anti-inflammatory activity. The dichloromethane extract (ID₅₀ 77 μg/cm²) as well compounds 1-11 (ID₅₀ 0.31-0.60 μmol/cm²) exhibited topical antiedematous properties comparable to those of indomethacin (ID₅₀ 0.29 μmol/cm²) in a mouse ear in vivo model. Two of the most potent compounds, 2-(2-hydroxy-4-methoxyphenyl)-5-(3-hydroxypropyl)benzofuran (5) and (+)-conocarpan (7), were studied regarding their time-dependent edema development and leukocyte infiltration up to 48 h after croton oil-induced dermatitis induction, and they showed activity profiles similar to that of hydrocortisone. In vitro studies of the isolated lignan derivatives demonstrated the inhibition of NF-κB, cyclooxygenase-1 and -2, 5-lipoxygenase, and microsomal prostaglandin E₂ synthase-1 as well as antioxidant properties, as mechanisms possibly contributing to the observed in vivo effects. The present findings not only support the ethnopharmacological use of K. lappacea roots but also reveal that the isolated lignan derivatives contribute strongly to the anti-inflammatory activity of this herbal drug.
|
Antiinflammatory activity in CD1 mouse ear dermatitis model assessed as reduction in leukocyte infiltration-based myeloperoxidase activity at 0.04 umol administered topically per cm'2 of ear measured 3 to 48 hrs post dermatitis induction relative to untreated control
|
Mus musculus
|
35.0
%
|
|
Journal : J. Nat. Prod.
Title : Lignan derivatives from Krameria lappacea roots inhibit acute inflammation in vivo and pro-inflammatory mediators in vitro.
Year : 2011
Volume : 74
Issue : 8
First Page : 1779
Last Page : 1786
Authors : Baumgartner L, Sosa S, Atanasov AG, Bodensieck A, Fakhrudin N, Bauer J, Favero GD, Ponti C, Heiss EH, Schwaiger S, Ladurner A, Widowitz U, Loggia RD, Rollinger JM, Werz O, Bauer R, Dirsch VM, Tubaro A, Stuppner H.
Abstract : The roots of Krameria lappacea are used traditionally against oropharyngeal inflammation. So far, the astringent and antimicrobial properties of its proanthocyanidin constituents are considered to account for the anti-inflammatory effect. The aim of the present study was to characterize pharmacologically a lipophilic extract of K. lappacea roots and several isolated lignan derivatives (1-11) in terms of their putative anti-inflammatory activity. The dichloromethane extract (ID₅₀ 77 μg/cm²) as well compounds 1-11 (ID₅₀ 0.31-0.60 μmol/cm²) exhibited topical antiedematous properties comparable to those of indomethacin (ID₅₀ 0.29 μmol/cm²) in a mouse ear in vivo model. Two of the most potent compounds, 2-(2-hydroxy-4-methoxyphenyl)-5-(3-hydroxypropyl)benzofuran (5) and (+)-conocarpan (7), were studied regarding their time-dependent edema development and leukocyte infiltration up to 48 h after croton oil-induced dermatitis induction, and they showed activity profiles similar to that of hydrocortisone. In vitro studies of the isolated lignan derivatives demonstrated the inhibition of NF-κB, cyclooxygenase-1 and -2, 5-lipoxygenase, and microsomal prostaglandin E₂ synthase-1 as well as antioxidant properties, as mechanisms possibly contributing to the observed in vivo effects. The present findings not only support the ethnopharmacological use of K. lappacea roots but also reveal that the isolated lignan derivatives contribute strongly to the anti-inflammatory activity of this herbal drug.
|
Antiinflammatory activity in CD1 mouse ear dermatitis model assessed as inhibition of Croton oil-induced ear edema at 0.01 umol administered topically per cm'2 of ear measured after induction of dermatitis relative to untreated control
|
Mus musculus
|
29.0
%
|
|
Journal : J. Nat. Prod.
Title : Lignan derivatives from Krameria lappacea roots inhibit acute inflammation in vivo and pro-inflammatory mediators in vitro.
Year : 2011
Volume : 74
Issue : 8
First Page : 1779
Last Page : 1786
Authors : Baumgartner L, Sosa S, Atanasov AG, Bodensieck A, Fakhrudin N, Bauer J, Favero GD, Ponti C, Heiss EH, Schwaiger S, Ladurner A, Widowitz U, Loggia RD, Rollinger JM, Werz O, Bauer R, Dirsch VM, Tubaro A, Stuppner H.
Abstract : The roots of Krameria lappacea are used traditionally against oropharyngeal inflammation. So far, the astringent and antimicrobial properties of its proanthocyanidin constituents are considered to account for the anti-inflammatory effect. The aim of the present study was to characterize pharmacologically a lipophilic extract of K. lappacea roots and several isolated lignan derivatives (1-11) in terms of their putative anti-inflammatory activity. The dichloromethane extract (ID₅₀ 77 μg/cm²) as well compounds 1-11 (ID₅₀ 0.31-0.60 μmol/cm²) exhibited topical antiedematous properties comparable to those of indomethacin (ID₅₀ 0.29 μmol/cm²) in a mouse ear in vivo model. Two of the most potent compounds, 2-(2-hydroxy-4-methoxyphenyl)-5-(3-hydroxypropyl)benzofuran (5) and (+)-conocarpan (7), were studied regarding their time-dependent edema development and leukocyte infiltration up to 48 h after croton oil-induced dermatitis induction, and they showed activity profiles similar to that of hydrocortisone. In vitro studies of the isolated lignan derivatives demonstrated the inhibition of NF-κB, cyclooxygenase-1 and -2, 5-lipoxygenase, and microsomal prostaglandin E₂ synthase-1 as well as antioxidant properties, as mechanisms possibly contributing to the observed in vivo effects. The present findings not only support the ethnopharmacological use of K. lappacea roots but also reveal that the isolated lignan derivatives contribute strongly to the anti-inflammatory activity of this herbal drug.
|
Antiinflammatory activity in CD1 mouse ear dermatitis model assessed as inhibition of Croton oil-induced ear edema at 0.03 umol administered topically per cm'2 of ear measured after induction of dermatitis relative to untreated control
|
Mus musculus
|
55.0
%
|
|
Journal : J. Nat. Prod.
Title : Lignan derivatives from Krameria lappacea roots inhibit acute inflammation in vivo and pro-inflammatory mediators in vitro.
Year : 2011
Volume : 74
Issue : 8
First Page : 1779
Last Page : 1786
Authors : Baumgartner L, Sosa S, Atanasov AG, Bodensieck A, Fakhrudin N, Bauer J, Favero GD, Ponti C, Heiss EH, Schwaiger S, Ladurner A, Widowitz U, Loggia RD, Rollinger JM, Werz O, Bauer R, Dirsch VM, Tubaro A, Stuppner H.
Abstract : The roots of Krameria lappacea are used traditionally against oropharyngeal inflammation. So far, the astringent and antimicrobial properties of its proanthocyanidin constituents are considered to account for the anti-inflammatory effect. The aim of the present study was to characterize pharmacologically a lipophilic extract of K. lappacea roots and several isolated lignan derivatives (1-11) in terms of their putative anti-inflammatory activity. The dichloromethane extract (ID₅₀ 77 μg/cm²) as well compounds 1-11 (ID₅₀ 0.31-0.60 μmol/cm²) exhibited topical antiedematous properties comparable to those of indomethacin (ID₅₀ 0.29 μmol/cm²) in a mouse ear in vivo model. Two of the most potent compounds, 2-(2-hydroxy-4-methoxyphenyl)-5-(3-hydroxypropyl)benzofuran (5) and (+)-conocarpan (7), were studied regarding their time-dependent edema development and leukocyte infiltration up to 48 h after croton oil-induced dermatitis induction, and they showed activity profiles similar to that of hydrocortisone. In vitro studies of the isolated lignan derivatives demonstrated the inhibition of NF-κB, cyclooxygenase-1 and -2, 5-lipoxygenase, and microsomal prostaglandin E₂ synthase-1 as well as antioxidant properties, as mechanisms possibly contributing to the observed in vivo effects. The present findings not only support the ethnopharmacological use of K. lappacea roots but also reveal that the isolated lignan derivatives contribute strongly to the anti-inflammatory activity of this herbal drug.
|
Antiinflammatory activity in CD1 mouse ear dermatitis model assessed as reduction in AUC of global leukocyte infiltration-based myeloperoxidase activity at 0.04 umol administered topically per cm'2 of ear measured 3 to 48 hrs post dermatitis induction relative to untreated control
|
Mus musculus
|
51.0
%
|
|
Journal : J. Nat. Prod.
Title : Lignan derivatives from Krameria lappacea roots inhibit acute inflammation in vivo and pro-inflammatory mediators in vitro.
Year : 2011
Volume : 74
Issue : 8
First Page : 1779
Last Page : 1786
Authors : Baumgartner L, Sosa S, Atanasov AG, Bodensieck A, Fakhrudin N, Bauer J, Favero GD, Ponti C, Heiss EH, Schwaiger S, Ladurner A, Widowitz U, Loggia RD, Rollinger JM, Werz O, Bauer R, Dirsch VM, Tubaro A, Stuppner H.
Abstract : The roots of Krameria lappacea are used traditionally against oropharyngeal inflammation. So far, the astringent and antimicrobial properties of its proanthocyanidin constituents are considered to account for the anti-inflammatory effect. The aim of the present study was to characterize pharmacologically a lipophilic extract of K. lappacea roots and several isolated lignan derivatives (1-11) in terms of their putative anti-inflammatory activity. The dichloromethane extract (ID₅₀ 77 μg/cm²) as well compounds 1-11 (ID₅₀ 0.31-0.60 μmol/cm²) exhibited topical antiedematous properties comparable to those of indomethacin (ID₅₀ 0.29 μmol/cm²) in a mouse ear in vivo model. Two of the most potent compounds, 2-(2-hydroxy-4-methoxyphenyl)-5-(3-hydroxypropyl)benzofuran (5) and (+)-conocarpan (7), were studied regarding their time-dependent edema development and leukocyte infiltration up to 48 h after croton oil-induced dermatitis induction, and they showed activity profiles similar to that of hydrocortisone. In vitro studies of the isolated lignan derivatives demonstrated the inhibition of NF-κB, cyclooxygenase-1 and -2, 5-lipoxygenase, and microsomal prostaglandin E₂ synthase-1 as well as antioxidant properties, as mechanisms possibly contributing to the observed in vivo effects. The present findings not only support the ethnopharmacological use of K. lappacea roots but also reveal that the isolated lignan derivatives contribute strongly to the anti-inflammatory activity of this herbal drug.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
98.24
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
113.79
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw swelling at 2 x 50 mg/kg, po administered 0.5 to 3 hrs prior to carrageenan challenge measured after 2.5 hrs by plethysmographic analysis relative to control
|
Rattus norvegicus
|
35.0
%
|
|
Journal : J. Med. Chem.
Title : Potential antiinflammatory compounds. 1. Antiinflammatory phenylpiperidine derivatives.
Year : 1979
Volume : 22
Issue : 12
First Page : 1460
Last Page : 1464
Authors : Hicks TA, Smith CE, Williamson WR, Day EH.
Abstract : The syntheses of a number of amines and their derivatives, based on the phenylpiperidine nucleus, are described. Their activities on the rat paw carrageenan test are also reported. Activities comparable to that of phenylbutazone were obtained for some of the amines, notably 4-piperidino-beta-methylphenethylamine.
|
Antiinflammatory activity in rat assessed as reduction of carrageenan-induced foot edema at 50 mg/kg, po administered as two doses
|
Rattus norvegicus
|
51.0
%
|
|
Journal : J. Med. Chem.
Title : Potential antiinflammatory compounds. 3. Compounds derived from acenaphthene and indan.
Year : 1979
Volume : 22
Issue : 12
First Page : 1464
Last Page : 1469
Authors : Smith CE, Williamson WR, Cashin CH, Kitchen EA.
Abstract : Compounds having acenaphthene and indan as their parent nuclei were synthesized for antiinflammatory testing. Compounds which showed activity were 1-phenyl-5-acenaphthenylacetic acid and its alpha-methyl derivative (carrageenan rat paw edema) and the same alpha-methylacenaphthenylacetic acid and 2-(4-chlorobenzylidene)-3-oxo-5-indanacetic acid and its alpha-methyl derivative (rat adjuvant arthritis). None of the compounds was more active than the control compounds phenylbutazone and indomethacin.
|
Antiinflammatory activity in rat assessed as inhibition of carrageenan-induced paw edema at 50 mg/kg, po administered as two doses 3 and 0.5 hr prior to challenge measured 2.5 hrs post challenge
|
Rattus norvegicus
|
42.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiinflammatory activity of some 2-aryl-6-benzoxazoleacetic acid derivatives.
Year : 1977
Volume : 20
Issue : 6
First Page : 797
Last Page : 801
Authors : Dunwell DW, Evans D.
Abstract : Various approaches to the synthesis of 2-aryl-6-substituted benzoxazoles are described. The products, which included the 6-methyl derivative 4a, ethylamines 10 and 19, ethanols 12 and 14, the acetic and alpha-methylacetic acids 9 and 16a--f, and the acetic ester 11, were screened for antiinflammatory activity on the carrageenan-induced rat paw edema test. Some of the compounds possessed activity superior to that of phenylbutazone and of the same order as that of benoxaprofen.
|
Displacement of 1 x 10'-8 M of [1,2,3-3H]-triamcinolone acetonide from glucocorticoid receptor in soluble fraction of mouse L929 cells after 20 hrs
|
Mus musculus
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological action of two glucocorticoid alkylating agents.
Year : 1977
Volume : 20
Issue : 9
First Page : 1134
Last Page : 1139
Authors : El Masry AH, Braun VC, Nielsen CJ, Pratt WB.
Abstract : Two alkylating glucocorticoids have been synthesized in order to test the possibility of alkylating glucocorticoid receptors. The title compounds are 9alpha-fluoro-11beta,16alpha,17alpha,21-tetrahydroxypregna-1,4-diene-3,20-dione 21-[bis(2-chloroethyl)carbamate] 16,17-acetonide (I) and 11beta,17alpha,21-trihydroxypregn-4-ene-3,20-dione 21-[bis(2-chloroethyl)carbamate] (II), prepared from triamcinolone acetonide and cortisol, respectively, through the reaction of the C-21 hydroxyl group with phosgene and di-2-chloroethylamine in the presence of triethylamine. Both compounds are biologically active as inhibitors of the growth of cultured mouse fibroblasts and are able to compete for the specific binding of radiolabeled triamcinolone acetonide to the L929 cell receptor. The bis(2-chloroethyl)carbamate moiety is capable of reacting with nucleophilic groups as evidenced by the colorimetric reaction with 4-(p-nitrobenzyl)pyridine. Both the interaction with the receptor and inhibition of cell growth by these two glucocorticoids are reversible.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of cotton pellet-induced granuloma formation at 10 mg/kg, po after 5 days relative to control
|
Rattus norvegicus
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : 4-(6-Methoxy-2-naphthyl)butan-2-one and related analogues, a novel structural class of antiinflammatory compounds.
Year : 1978
Volume : 21
Issue : 12
First Page : 1260
Last Page : 1264
Authors : Goudie AC, Gaster LM, Lake AW, Rose CJ, Freeman PC, Hughes BO, Miller D.
Abstract : A series of compounds related to 4-(6-methoxy-2-naphthyl)butan-2-one has been prepared and tested for antiinflammatory activity by the cotton pellet granuloma method. Compounds possessing a small lipophilic group such as methoxyl, methyl, or chloro in the 6 position in conjunction with a butan-2-one side chain in the 2 position of the naphthalene ring were most active. The indtroduction of a methyl group along the side chain was invariably deleterious. Good activity was generally retained by forming esters of a butan-2-ol side chain.
|
Anti-inflammatory activity in mouse RAW264.7 cells assessed as inhibition of LPS-induced thromboxane B2 production at 10 uM incubated for 48 hrs by ELISA method
|
Mus musculus
|
42.0
%
|
|
Journal : J. Nat. Prod.
Title : Guaianolides and a seco-Eudesmane from the Resinous Exudates of Cushion Bush (Leucophyta brownii) and Evaluation of Their Cytostatic and Anti-inflammatory Activity.
Year : 2015
Volume : 78
Issue : 8
First Page : 1877
Last Page : 1885
Authors : Hyldgaard MG, Purup S, Bond AD, Fretté XC, Qu H, Jensen KT, Christensen LP.
Abstract : A detailed phytochemical investigation of a dichloromethane extract of the resinous exudates of the cushion bush plant (Leucophyta brownii) resulted in the isolation of the new 8,12-guaianolides leucophytalins A (5) and B (6), the new 1,10-seco-eudesmane leucophytalin C (10), six rare 8,12-guaianolides (1-4, 7, and 8), and the xanthanolide tomentosin (9). The structures of all isolated compounds were elucidated on the basis of spectroscopic and spectrometric analyses. The structures of compounds isolated in crystalline form, including leucophytalins A and C, were further confirmed by X-ray crystallography. The crude extract exhibited moderate cytostatic activity against a breast cancer (MCF-7) and human colon cancer (HT-29) cell line with IC₅₀ values of 9.3 and 18 μg/mL, respectively, and anti-inflammatory activity against the macrophage-like cell line RAW 264.7 with IC₅₀ values of 3.9 and 6.1 μg/mL for thromboxane B2 and prostaglandin E2 production, respectively. The isolated compounds were evaluated for their cytostatic activity against MCF-7 and HT-29 cells (1, 3-10) and their anti-inflammatory activity against RAW 264.7 cells (1-10). All isolated compounds are most likely derived from (+)-germacrene A, and a biosynthetic pathway is proposed for these sesquiterpenoids.
|
Anti-inflammatory activity in mouse RAW264.7 cells assessed as inhibition of LPS-induced prostaglandin E2 production at 10 uM incubated for 48 hrs by ELISA method
|
Mus musculus
|
21.0
%
|
|
Journal : J. Nat. Prod.
Title : Guaianolides and a seco-Eudesmane from the Resinous Exudates of Cushion Bush (Leucophyta brownii) and Evaluation of Their Cytostatic and Anti-inflammatory Activity.
Year : 2015
Volume : 78
Issue : 8
First Page : 1877
Last Page : 1885
Authors : Hyldgaard MG, Purup S, Bond AD, Fretté XC, Qu H, Jensen KT, Christensen LP.
Abstract : A detailed phytochemical investigation of a dichloromethane extract of the resinous exudates of the cushion bush plant (Leucophyta brownii) resulted in the isolation of the new 8,12-guaianolides leucophytalins A (5) and B (6), the new 1,10-seco-eudesmane leucophytalin C (10), six rare 8,12-guaianolides (1-4, 7, and 8), and the xanthanolide tomentosin (9). The structures of all isolated compounds were elucidated on the basis of spectroscopic and spectrometric analyses. The structures of compounds isolated in crystalline form, including leucophytalins A and C, were further confirmed by X-ray crystallography. The crude extract exhibited moderate cytostatic activity against a breast cancer (MCF-7) and human colon cancer (HT-29) cell line with IC₅₀ values of 9.3 and 18 μg/mL, respectively, and anti-inflammatory activity against the macrophage-like cell line RAW 264.7 with IC₅₀ values of 3.9 and 6.1 μg/mL for thromboxane B2 and prostaglandin E2 production, respectively. The isolated compounds were evaluated for their cytostatic activity against MCF-7 and HT-29 cells (1, 3-10) and their anti-inflammatory activity against RAW 264.7 cells (1-10). All isolated compounds are most likely derived from (+)-germacrene A, and a biosynthetic pathway is proposed for these sesquiterpenoids.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 1 hr relative to control
|
Homo sapiens
|
3.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 2 hrs relative to control
|
Homo sapiens
|
6.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 3 hrs relative to control
|
Homo sapiens
|
4.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 4 hrs relative to control
|
Homo sapiens
|
-1.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 16 hrs relative to control
|
Homo sapiens
|
5.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 24 hrs relative to control
|
Homo sapiens
|
12.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts at 60 nM preincubated for 6 hrs followed by [3H]-dexamethasone addition relative to control
|
Homo sapiens
|
69.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts using buffer solution without beta-mercaptoethanol at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 1 hr relative to control
|
Homo sapiens
|
-16.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts using buffer solution without beta-mercaptoethanol at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 2 hrs relative to control
|
Homo sapiens
|
-15.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts using buffer solution without beta-mercaptoethanol at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 3 hrs relative to control
|
Homo sapiens
|
-23.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts using buffer solution without beta-mercaptoethanol at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 4 hrs relative to control
|
Homo sapiens
|
-12.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts using buffer solution without beta-mercaptoethanol at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 16 hrs relative to control
|
Homo sapiens
|
16.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts using buffer solution without beta-mercaptoethanol at 60 nM preincubated for 6 hrs followed by washout and second incubation with [3H]-dexamethasone for 24 hrs relative to control
|
Homo sapiens
|
-8.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Displacement of [3H]-dexamethasone from GR receptor in human IM-9 cytosolic extracts using buffer solution without beta-mercaptoethanol at 60 nM preincubated for 6 hrs followed by [3H]-dexamethasone addition relative to control
|
Homo sapiens
|
69.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition.
Year : 2016
Volume : 26
Issue : 20
First Page : 5032
Last Page : 5038
Authors : Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H.
Abstract : The synthesis and in vitro properties of six analogues of the selective glucocorticoid receptor (GR) agonist GSK866, bearing a warhead for covalent linkage to the glucocorticoid receptor, is described.
|
Antiinflammatory activity in BALB/c mouse assessed as inhibition of TPA-induced ear edema applied topically pretreated for 30 mins followed by TPA exposure measured after 4 hrs
|
Mus musculus
|
56.33
%
|
|
Journal : J Nat Prod
Title : Chlojaponilactone B from Chloranthus japonicus: Suppression of Inflammatory Responses via Inhibition of the NF-κB Signaling Pathway.
Year : 2016
Volume : 79
Issue : 9
First Page : 2257
Last Page : 2263
Authors : Zhao JJ, Guo YQ, Yang DP, Xue X, Liu Q, Zhu LP, Yin S, Zhao ZM.
Abstract : Bioassay-guided fractionation of an ethanolic extract of Chloranthus japonicus led to the isolation of the known lindenane-type sesquiterpenoid chlojaponilactone B (1). This compound exhibited pronounced inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Further anti-inflammatory assays showed that 1 suppressed the levels of some key inflammation mediators, such as iNOS, TNF-α, and IL-6, in a dose-dependent manner, and reduced the ear thickness and neutrophil infiltration in 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated mice. A mechanistic study revealed that compound 1 exerted its anti-inflammatory effects via the suppression of the NF-κB signaling pathway, which inhibited NF-κB-dependent transcriptional activity, IκBα phosphorylation, and p65 nuclear translocation. In contrast, chlojaponilactone B (1) was found to exert little influence on the MAPK signaling pathway.
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Binding affinity to MR (unknown origin)
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Homo sapiens
|
0.5
nM
|
|
Journal : J Med Chem
Title : Modulating Mineralocorticoid Receptor with Non-steroidal Antagonists. New Opportunities for the Development of Potent and Selective Ligands without Off-Target Side Effects.
Year : 2017
Volume : 60
Issue : 7
First Page : 2629
Last Page : 2650
Authors : Martín-Martínez M, Pérez-Gordillo FL, Álvarez de la Rosa D, Rodríguez Y, Gerona-Navarro G, González-Muñiz R, Zhou MM.
Abstract : Steroidal mineralocorticoid receptor (MR) antagonists are used for treatment of a range of human diseases, but they present challenging issues of complex chemical synthesis, undesirable physical properties, and poor selectivity along with unwanted side effects. Therefore, there is a great interest in the discovery of non-steroidal ligands able to bind to the ligand-binding domain of the MR and recruit different co-regulators to produce tissue-specific therapeutic effects. Several academic groups and pharmaceutical companies have been developing a series of non-steroidal ligands that consist of different chemical scaffolds, yielding MR antagonists currently evaluated in clinical studies for the treatment of congestive heart failure, hypertension, or diabetic nephropathy. The main focus of this Perspective is to review the reported structure-activity relationships of the different series of compounds, as well as the structural studies that contribute to a better understanding of the receptor active site and are also helpful for optimization processes.
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Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
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Staphylococcus aureus subsp. aureus
|
7.72
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
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Escherichia coli
|
3.33
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
5.06
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
10.83
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
3.9
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
1.65
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-3.64
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
52.93
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.45
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
1.1
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
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Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.1
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
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Agonist activity at glucocorticoid receptor in rat INS-1 832/13 cells transfected with CCL2-promoter luciferase plasmid construct assessed as reduction in IL-1 beta induced inflammation by luciferase reporter gene assay
|
Rattus norvegicus
|
25.12
nM
|
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