|
Inhibitory activity against partially purified rat liver HMG-CoA reductase in vitro; 0.23-0.71
|
None
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : HMG-CoA reductase inhibitors: design, synthesis, and biological activity of tetrahydroindazole-substituted 3,5-dihydroxy-6-heptenoic acid sodium salts.
Year : 1993
Volume : 36
Issue : 23
First Page : 3674
Last Page : 3685
Authors : Connolly PJ, Westin CD, Loughney DA, Minor LK.
Abstract : Compounds comprising a series of 7-[2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5- dihydroxy-6-heptenoic acid sodium salts (18) were synthesized and tested for their ability to inhibit HMG-CoA reductase in a partially purified enzyme preparation and cholesterol biosynthesis from acetate in cultured HEP-G2 cells. Changing the size of the saturated ring of the tetrahydroindazole nucleus did not improve potency, but incorporation of substituents at the 7-position resulted in up to 1700-fold improvement in inhibitory potency. Structure-activity studies revealed that the most potent compounds possess a substituted benzyl group at the 7-position, with a preference for steric bulk at the para position of the benzene ring. The most potent enzyme inhibitor (18t, IC50 = 3.0 nM) is approximately 3-fold more potent than lovastin sodium salt (2). The most potent cholesterol biosynthesis inhibitor in HEP-G2 cells (18q, IC50 = 0.078 microM) is slightly less potent than 2 (sodium salt). Molecular modeling studies suggested that, when compared to the parent compound (18b) lacking the appropriate 7-substituent, 18t overlaps better with 2 and literature inhibitors 5 and 6 in a hydrophobic binding region adjacent to the enzyme active site.
|
Inhibition of microsomal rat liver HMG-CoA reductase
|
None
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The design and biological evaluation of a series of 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitors related to dihydromevinolin.
Year : 1992
Volume : 2
Issue : 3
First Page : 223
Last Page : 228
Authors : Bone EA, Cunningham EM, Davidson AH, Galloway W, Lewis CN, Morrice EM, Reeve MM, Todd RS, White IM
|
Tested for inhibition of rat liver microsomal HMG-CoA reductase
|
None
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of bile acid-derived HMG-CoA reductase inhibitors. The role of 21-methyl in recognition of HMG-CoA reductase and the ileal bile acid transport system.
Year : 1994
Volume : 37
Issue : 20
First Page : 3240
Last Page : 3246
Authors : Wess G, Kramer W, Han XB, Bock K, Enhsen A, Glombik H, Baringhaus KH, Böger G, Urmann M, Hoffmann A.
Abstract : To increase hepatoselectivity of HMG-CoA reductase inhibitors by using the specific bile acid transport systems, deoxycholic acid-derived inhibitors 9 and 11 have been synthesized, on the basis of the concept of combining in one molecule structural requirements for specific inhibition of the HMG-CoA reductase and specific recognition by the ileal bile acid transport system. The 1-methyl-3-carboxylpropyl subunit of deoxycholic acid was replaced by the 3,5-dihydroxyheptanoic acid lactone of lovastatin, and position 12-OH was esterified with 2-methylbutyric acid. Compounds 9 and 11 were evaluated for their inhibitory activity on rat liver HMG-CoA reductase, cholesterol biosynthesis in HEP G2 cells, and [3H]taurocholate uptake in rabbit brush border membrane vesicles and compared with methyl derivatives 8 and 10. The steroidal 21-CH3 group affects both activity on HMG-CoA reductase and recognition by the ileal bile acid transport system.
|
Tested in vitro for the HMG-CoA reductase inhibitory activity in a microsomal preparation
|
None
|
530.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and biological evaluation of a series of thiophene-based 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors
Year : 1997
Volume : 7
Issue : 5
First Page : 549
Last Page : 554
Authors : Coppola GM, Damon RE, Yu H, Engstrom RG, Scallen TJ
|
In vitro inhibitory activity against isolated enzyme HMG-CoA reductase
|
None
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of tetrazol-1-yl analogs of HMG-COA reductase inhibitor BMS180431 (formerly BMY21950)
Year : 1992
Volume : 2
Issue : 9
First Page : 1085
Last Page : 1088
Authors : Sit S, Parker RA, Wright J
|
Inhibition of the incorporation of sodium [14C]acetate into cholesterol in HEP G2 cells.
|
None
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of new HMG-CoA reductase inhibitors. 3. Lactones of 6-phenoxy-3,5-dihydroxyhexanoic acids.
Year : 1991
Volume : 34
Issue : 10
First Page : 2962
Last Page : 2983
Authors : Jendralla H, Granzer E, von Kerekjarto B, Krause R, Schacht U, Baader E, Bartmann W, Beck G, Bergmann A, Kesseler K.
Abstract : A group of 43 optically active sodium carboxylates (11a-qq and the corresponding lactones 4 were prepared from respective phenols 8 according to Schemes I-III. Phenols 8 were synthesized from commercially available compounds according to Schemes IV-IX. A number of these HMG-CoA reductase inhibitors 11 exceeded mevinolin's activity in vitro (Tables II and III). Selected lactones 4 effectively inhibited hepatic "de novo" cholesterol synthesis in rats in vivo (Table IV). After po administration to rabbits, 4ff(11ff), 4hh, and notably 11jj reduced plasma cholesterol levels more potently than mevinolin (Table V). Whereas 4ff(11ff) displayed the slight superiority expected according to in vitro data, 4hh and 11jj were considerably more potent than expected. Each of these compounds had only moderate activity after po administration to dogs (Table VI). Compound di-11ii, a hybrid of the structural elements of probucol and HMG-CoA reductase inhibitors, after po administration to rats decreased serum lipoproteins and increased HDL/LDL ratio better than probucol (Table VII). HMG-CoA reductase inhibitor 11ll and phenolic building blocks 8, notably 8jj and 8kk, inhibited LDL oxidation in vitro (Table VIII). Chemical structure-activity relationships (Table IX) and the pharmacological profile of phenoxy-type inhibitors 11 diverged from those of known HMG-CoA reductase inhibitors.
|
Tested for ability to inhibit incorporation of [14C]acetate into cholesterol in cultured human hepatoma (HEP-G2) cells; 0.061-0.10
|
Homo sapiens
|
79.0
nM
|
|
Journal : J. Med. Chem.
Title : HMG-CoA reductase inhibitors: design, synthesis, and biological activity of tetrahydroindazole-substituted 3,5-dihydroxy-6-heptenoic acid sodium salts.
Year : 1993
Volume : 36
Issue : 23
First Page : 3674
Last Page : 3685
Authors : Connolly PJ, Westin CD, Loughney DA, Minor LK.
Abstract : Compounds comprising a series of 7-[2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5- dihydroxy-6-heptenoic acid sodium salts (18) were synthesized and tested for their ability to inhibit HMG-CoA reductase in a partially purified enzyme preparation and cholesterol biosynthesis from acetate in cultured HEP-G2 cells. Changing the size of the saturated ring of the tetrahydroindazole nucleus did not improve potency, but incorporation of substituents at the 7-position resulted in up to 1700-fold improvement in inhibitory potency. Structure-activity studies revealed that the most potent compounds possess a substituted benzyl group at the 7-position, with a preference for steric bulk at the para position of the benzene ring. The most potent enzyme inhibitor (18t, IC50 = 3.0 nM) is approximately 3-fold more potent than lovastin sodium salt (2). The most potent cholesterol biosynthesis inhibitor in HEP-G2 cells (18q, IC50 = 0.078 microM) is slightly less potent than 2 (sodium salt). Molecular modeling studies suggested that, when compared to the parent compound (18b) lacking the appropriate 7-substituent, 18t overlaps better with 2 and literature inhibitors 5 and 6 in a hydrophobic binding region adjacent to the enzyme active site.
|
Concentration required to inhibit HMG-CoA reductase by 50% was determined in HES 9 cell line
|
Homo sapiens
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of dihydroeptastatin, a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
Year : 1992
Volume : 35
Issue : 18
First Page : 3388
Last Page : 3393
Authors : Bone EA, Davidson AH, Lewis CN, Todd RS.
Abstract : The total synthesis of the novel hydroxylated HMG-CoA reductase inhibitor dihydroeptastatin (7) is described. The key C-3 hydroxyl group is introduced via a Baeyer-Villiger reaction on the methyl ketone 17 which is obtained in three high-yielding steps from the known tricyclic lactone 12. In an isolated enzyme assay dihydroeptastatin had a similar IC50 to mevinolin but in cellular assays using Hep G2 and HES 9 cell lines, dihydroeptastatin was much less potent. No selectivity between the two cell lines was observed.
|
Tested in vitro for the inhibition of HMG-CoA reductase from partially purified microsomal preparations.
|
Canis lupus familiaris
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of cholesterol biosynthesis. 6. trans-6-[2-(2-N-heteroaryl-3,5-disubstituted- pyrazol-4-yl)ethyl/ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones.
Year : 1992
Volume : 35
Issue : 11
First Page : 2095
Last Page : 2103
Authors : Sliskovic DR, Blankley CJ, Krause BR, Newton RS, Picard JA, Roark WH, Roth BD, Sekerke C, Shaw MK, Stanfield RL.
Abstract : A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). Two compounds 20a and 20b, were more potent than lovastatin at inhibiting cholesterol biosynthesis both in vitro and in vivo. In terms of plasma cholesterol lowering, 20a was much more efficacious than lovastatin. In addition to possessing increased biological activity, these compounds are significantly less lipophilic than lovastatin, in fact, 20b has a CLOGP value comparable to pravastatin.
|
Compound was evaluated for inhibitory activity against HMG-CoA reductase in HepG2 cells
|
None
|
39.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of tetrazol-1-yl analogs of HMG-COA reductase inhibitor BMS180431 (formerly BMY21950)
Year : 1992
Volume : 2
Issue : 9
First Page : 1085
Last Page : 1088
Authors : Sit S, Parker RA, Wright J
|
Concentration required to inhibit HMG-CoA reductase by 50% was determined in Hep G2 cell line
|
None
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of dihydroeptastatin, a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
Year : 1992
Volume : 35
Issue : 18
First Page : 3388
Last Page : 3393
Authors : Bone EA, Davidson AH, Lewis CN, Todd RS.
Abstract : The total synthesis of the novel hydroxylated HMG-CoA reductase inhibitor dihydroeptastatin (7) is described. The key C-3 hydroxyl group is introduced via a Baeyer-Villiger reaction on the methyl ketone 17 which is obtained in three high-yielding steps from the known tricyclic lactone 12. In an isolated enzyme assay dihydroeptastatin had a similar IC50 to mevinolin but in cellular assays using Hep G2 and HES 9 cell lines, dihydroeptastatin was much less potent. No selectivity between the two cell lines was observed.
|
Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)
|
None
|
0.05
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of new HMG-CoA reductase inhibitors. 2. Derivatives of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)-enoic (-heptanoic) acids.
Year : 1990
Volume : 33
Issue : 1
First Page : 61
Last Page : 70
Authors : Jendralla H, Baader E, Bartmann W, Beck G, Bergmann A, Granzer E, von Kerekjarto B, Kesseler K, Krause R, Schubert W.
Abstract : A series of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)- enoates (-heptanoates) 1 and 2 have been prepared and tested for inhibiti 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The most potent compounds exceeded mevinolin's activity in vitro and in vivo.
|
Inhibition of cellular HMG-CoA reductase in cultures of human HEP G2 cells, determined by decreased incorporation of sodium [14C]acetate into cholesterol.
|
None
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids.
Year : 1990
Volume : 33
Issue : 1
First Page : 52
Last Page : 60
Authors : Beck G, Kesseler K, Baader E, Bartmann W, Bergmann A, Granzer E, Jendralla H, von Kerekjarto B, Krause R, Paulus E.
Abstract : Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids 2-4 have been synthesized. Extensive exploration of structure-activity relationships led to several compounds exceeding the inhibitory activity of mevinolin (1b) on HMG-CoA reductase, both in vitro and in vivo. First clinical trials with 2i (HR 780) are in preparation.
|
Compound was evaluated for inhibitory activity against HMG-CoA reductase from rat hepatocyte
|
None
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of tetrazol-1-yl analogs of HMG-COA reductase inhibitor BMS180431 (formerly BMY21950)
Year : 1992
Volume : 2
Issue : 9
First Page : 1085
Last Page : 1088
Authors : Sit S, Parker RA, Wright J
|
Compound was evaluated for the inhibition of HMG-CoA reductase (COR) in rats.
|
None
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of cholesterol biosynthesis. 4. trans-6-[2-(substituted-quinolinyl)ethenyl/ethyl]tetrahydro-4-hydroxy-2 H-pyran-2-ones, a novel series of HMG-CoA reductase inhibitors.
Year : 1991
Volume : 34
Issue : 1
First Page : 367
Last Page : 373
Authors : Sliskovic DR, Picard JA, Roark WH, Roth BD, Ferguson E, Krause BR, Newton RS, Sekerke C, Shaw MK.
Abstract : A series of substituted quinoline mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and (cholesterol biosynthesis) in vivo. Since previous studies suggested that the 4-(4-fluorophenyl) and 2-(1-methylethyl) substituents afforded optimum potency, attention was focused on variations at position 6 of the quinoline ring. Biological evaluation of a small number of analogues bearing a variety of 6-substituents showed that modification at this position had little effect on potency. Several compounds (8b, 8e, and 11) were identified that showed comparable potency to compactin and mevinolin in both the in vitro and in vivo assays.
|
In vitro inhibition of HMG-CoA reductase in solubilized rat liver.
|
None
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of new HMG-CoA reductase inhibitors. 3. Lactones of 6-phenoxy-3,5-dihydroxyhexanoic acids.
Year : 1991
Volume : 34
Issue : 10
First Page : 2962
Last Page : 2983
Authors : Jendralla H, Granzer E, von Kerekjarto B, Krause R, Schacht U, Baader E, Bartmann W, Beck G, Bergmann A, Kesseler K.
Abstract : A group of 43 optically active sodium carboxylates (11a-qq and the corresponding lactones 4 were prepared from respective phenols 8 according to Schemes I-III. Phenols 8 were synthesized from commercially available compounds according to Schemes IV-IX. A number of these HMG-CoA reductase inhibitors 11 exceeded mevinolin's activity in vitro (Tables II and III). Selected lactones 4 effectively inhibited hepatic "de novo" cholesterol synthesis in rats in vivo (Table IV). After po administration to rabbits, 4ff(11ff), 4hh, and notably 11jj reduced plasma cholesterol levels more potently than mevinolin (Table V). Whereas 4ff(11ff) displayed the slight superiority expected according to in vitro data, 4hh and 11jj were considerably more potent than expected. Each of these compounds had only moderate activity after po administration to dogs (Table VI). Compound di-11ii, a hybrid of the structural elements of probucol and HMG-CoA reductase inhibitors, after po administration to rats decreased serum lipoproteins and increased HDL/LDL ratio better than probucol (Table VII). HMG-CoA reductase inhibitor 11ll and phenolic building blocks 8, notably 8jj and 8kk, inhibited LDL oxidation in vitro (Table VIII). Chemical structure-activity relationships (Table IX) and the pharmacological profile of phenoxy-type inhibitors 11 diverged from those of known HMG-CoA reductase inhibitors.
|
In vitro inhibition of HMG-CoA reductase of rat liver
|
None
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of new HMG-CoA reductase inhibitors. 2. Derivatives of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)-enoic (-heptanoic) acids.
Year : 1990
Volume : 33
Issue : 1
First Page : 61
Last Page : 70
Authors : Jendralla H, Baader E, Bartmann W, Beck G, Bergmann A, Granzer E, von Kerekjarto B, Kesseler K, Krause R, Schubert W.
Abstract : A series of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)- enoates (-heptanoates) 1 and 2 have been prepared and tested for inhibiti 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The most potent compounds exceeded mevinolin's activity in vitro and in vivo.
|
Inhibition of rat liver microsomal HMG-CoA reductase
|
Rattus norvegicus
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of cholesterol biosynthesis. 2. 3,5-Dihydroxy-7-(N-pyrrolyl)-6-heptenoates, a novel series of HMG-CoA reductase inhibitors.
Year : 1993
Volume : 36
Issue : 23
First Page : 3658
Last Page : 3662
Authors : Procopiou PA, Draper CD, Hutson JL, Inglis GG, Ross BC, Watson NS.
Abstract : A series of 7-[2,3-diaryl-5-(1-methylethyl)-1H-pyrrol-1-yl]-3,5- dihydroxy-6-heptenoates was prepared and evaluated for its ability to inhibit the enzyme HMG-CoA reductase in vitro. Maintaining a 5-(1-methylethyl) substituent found to be optimal in related studies, structure-activity relationships were established for compounds modified at positions 2, 3, and 4 of the pyrrole ring. The 4-fluorophenyl group was preferred at the pyrrole 2-position, while incorporation of a range of substituted phenyl groups and pyridyl substituents at the 3-position provided compounds with equivalent enzyme inhibitory activities and widely different lipophilicities. Pentasubstituted pyrrole 3h was found to have a 10-fold greater potency than lovastatin.
|
In vitro inhibition of rat liver HMG-CoA reductase
|
None
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids.
Year : 1990
Volume : 33
Issue : 1
First Page : 52
Last Page : 60
Authors : Beck G, Kesseler K, Baader E, Bartmann W, Bergmann A, Granzer E, Jendralla H, von Kerekjarto B, Krause R, Paulus E.
Abstract : Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids 2-4 have been synthesized. Extensive exploration of structure-activity relationships led to several compounds exceeding the inhibitory activity of mevinolin (1b) on HMG-CoA reductase, both in vitro and in vivo. First clinical trials with 2i (HR 780) are in preparation.
|
In vitro inhibitory activity was measured against rat liver HMG-CoA reductase
|
None
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
Year : 1990
Volume : 33
Issue : 11
First Page : 2982
Last Page : 2999
Authors : Sit SY, Parker RA, Motoc I, Han W, Balasubramanian N, Catt JD, Brown PJ, Harte WE, Thompson MD, Wright JJ.
Abstract : A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.
|
In vitro inhibitory activity was measured against rat liver HMG-CoA reductase using [2-14C]-acetate incorporation
|
None
|
32.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
Year : 1990
Volume : 33
Issue : 11
First Page : 2982
Last Page : 2999
Authors : Sit SY, Parker RA, Motoc I, Han W, Balasubramanian N, Catt JD, Brown PJ, Harte WE, Thompson MD, Wright JJ.
Abstract : A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.
|
Tested for inhibition of cholesterol biosynthesis in HEP G2 cells
|
Homo sapiens
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of bile acid-derived HMG-CoA reductase inhibitors. The role of 21-methyl in recognition of HMG-CoA reductase and the ileal bile acid transport system.
Year : 1994
Volume : 37
Issue : 20
First Page : 3240
Last Page : 3246
Authors : Wess G, Kramer W, Han XB, Bock K, Enhsen A, Glombik H, Baringhaus KH, Böger G, Urmann M, Hoffmann A.
Abstract : To increase hepatoselectivity of HMG-CoA reductase inhibitors by using the specific bile acid transport systems, deoxycholic acid-derived inhibitors 9 and 11 have been synthesized, on the basis of the concept of combining in one molecule structural requirements for specific inhibition of the HMG-CoA reductase and specific recognition by the ileal bile acid transport system. The 1-methyl-3-carboxylpropyl subunit of deoxycholic acid was replaced by the 3,5-dihydroxyheptanoic acid lactone of lovastatin, and position 12-OH was esterified with 2-methylbutyric acid. Compounds 9 and 11 were evaluated for their inhibitory activity on rat liver HMG-CoA reductase, cholesterol biosynthesis in HEP G2 cells, and [3H]taurocholate uptake in rabbit brush border membrane vesicles and compared with methyl derivatives 8 and 10. The steroidal 21-CH3 group affects both activity on HMG-CoA reductase and recognition by the ileal bile acid transport system.
|
Compound was tested for its Cholesterol Synthesis Inhibition ability in rats.
|
Rattus norvegicus
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of cholesterol biosynthesis. 4. trans-6-[2-(substituted-quinolinyl)ethenyl/ethyl]tetrahydro-4-hydroxy-2 H-pyran-2-ones, a novel series of HMG-CoA reductase inhibitors.
Year : 1991
Volume : 34
Issue : 1
First Page : 367
Last Page : 373
Authors : Sliskovic DR, Picard JA, Roark WH, Roth BD, Ferguson E, Krause BR, Newton RS, Sekerke C, Shaw MK.
Abstract : A series of substituted quinoline mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and (cholesterol biosynthesis) in vivo. Since previous studies suggested that the 4-(4-fluorophenyl) and 2-(1-methylethyl) substituents afforded optimum potency, attention was focused on variations at position 6 of the quinoline ring. Biological evaluation of a small number of analogues bearing a variety of 6-substituents showed that modification at this position had little effect on potency. Several compounds (8b, 8e, and 11) were identified that showed comparable potency to compactin and mevinolin in both the in vitro and in vivo assays.
|
Compound was evaluated for the percentage of acute inhibition of cholesterol synthesis (AICS) in male rats through peroral rout.
|
Rattus norvegicus
|
72.0
%
|
|
Journal : J. Med. Chem.
Title : Inhibitors of cholesterol biosynthesis. 4. trans-6-[2-(substituted-quinolinyl)ethenyl/ethyl]tetrahydro-4-hydroxy-2 H-pyran-2-ones, a novel series of HMG-CoA reductase inhibitors.
Year : 1991
Volume : 34
Issue : 1
First Page : 367
Last Page : 373
Authors : Sliskovic DR, Picard JA, Roark WH, Roth BD, Ferguson E, Krause BR, Newton RS, Sekerke C, Shaw MK.
Abstract : A series of substituted quinoline mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and (cholesterol biosynthesis) in vivo. Since previous studies suggested that the 4-(4-fluorophenyl) and 2-(1-methylethyl) substituents afforded optimum potency, attention was focused on variations at position 6 of the quinoline ring. Biological evaluation of a small number of analogues bearing a variety of 6-substituents showed that modification at this position had little effect on potency. Several compounds (8b, 8e, and 11) were identified that showed comparable potency to compactin and mevinolin in both the in vitro and in vivo assays.
|
Inhibition of hepatic cholesterol de novo synthesis in male rats after po administration,
|
Rattus norvegicus
|
14.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of new HMG-CoA reductase inhibitors. 2. Derivatives of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)-enoic (-heptanoic) acids.
Year : 1990
Volume : 33
Issue : 1
First Page : 61
Last Page : 70
Authors : Jendralla H, Baader E, Bartmann W, Beck G, Bergmann A, Granzer E, von Kerekjarto B, Kesseler K, Krause R, Schubert W.
Abstract : A series of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)- enoates (-heptanoates) 1 and 2 have been prepared and tested for inhibiti 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The most potent compounds exceeded mevinolin's activity in vitro and in vivo.
|
The compound was tested in vivo for the inhibition of cholesterol biosynthesis in chow-fed rats at 1.0 mg/kg.
|
Rattus norvegicus
|
64.0
%
|
|
Journal : J. Med. Chem.
Title : Inhibitors of cholesterol biosynthesis. 6. trans-6-[2-(2-N-heteroaryl-3,5-disubstituted- pyrazol-4-yl)ethyl/ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones.
Year : 1992
Volume : 35
Issue : 11
First Page : 2095
Last Page : 2103
Authors : Sliskovic DR, Blankley CJ, Krause BR, Newton RS, Picard JA, Roark WH, Roth BD, Sekerke C, Shaw MK, Stanfield RL.
Abstract : A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). Two compounds 20a and 20b, were more potent than lovastatin at inhibiting cholesterol biosynthesis both in vitro and in vivo. In terms of plasma cholesterol lowering, 20a was much more efficacious than lovastatin. In addition to possessing increased biological activity, these compounds are significantly less lipophilic than lovastatin, in fact, 20b has a CLOGP value comparable to pravastatin.
|
Inhibition of v-ras posttranslational processing in NIH3T3 cells at 15 uM
|
Mus musculus
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Pseudopeptide inhibitors of Ras farnesyl-protein transferase.
Year : 1994
Volume : 37
Issue : 6
First Page : 725
Last Page : 732
Authors : Graham SL, deSolms SJ, Giuliani EA, Kohl NE, Mosser SD, Oliff AI, Pompliano DL, Rands E, Breslin MJ, Deana AA.
Abstract : Inhibitors of Ras farnesyl-protein transferase are described. These are reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation. Deletion of the carbonyl groups between the first two residues of the tetrapeptides either preserves or improves activity, depending on the peptide sequence. The most potent in vitro enzyme inhibitor described (IC50 = 5 nM) is Cys [psi CH2NH]Ile[psi CH2NH]Phe-Met (3). To obtain compounds able to suppress Ras farnesylation in cell culture, further structural modification to include a homoserine lactone prodrug was required. Compound 18 (Cys[psi CH2NH]Ile[psi CH2NH]Ile-homoserine lactone) reduced the extent of Ras farnesylation by 50% in NIH3T3 fibroblasts in culture at a concentration of 50 microM. Structure-activity studies also led to 12 (Cys[psi CH2NH]Val-Ile-Leu), a potent and selective inhibitor of a related enzyme, the type-I geranylgeranyl protein transferase.
|
Inhibition of human HMGCoA reductase
|
Homo sapiens
|
0.6
nM
|
|
Inhibition of human HMGCoA reductase
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Nat. Prod.
Title : Novel Acetylenic Acids from the Root Bark of Paramacrolobium caeruleum: Inhibitors of 3-Hydroxy-3-methyl-glutaryl Coenzyme A Reductase
Year : 1989
Volume : 52
Issue : 1
First Page : 153
Last Page : 161
Authors : Patil AD, Chan JA, Lois-Flamberg P, Mayer RJ, Westley JW
|
Inhibition of sICAM1/LFA1 interaction-mediated human THP1 cell adhesion after 1 hr by ELISA
|
Homo sapiens
|
8.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Alkamides from the fruits of Piper longum and Piper nigrum displaying potent cell adhesion inhibition.
Year : 2008
Volume : 18
Issue : 16
First Page : 4544
Last Page : 4546
Authors : Lee SW, Kim YK, Kim K, Lee HS, Choi JH, Lee WS, Jun CD, Park JH, Lee JM, Rho MC.
Abstract : Eight alkamides 1-8 were isolated by bioassay-guided isolation of EtOH extracts of the fruits of Piper longum and Piper nigum (Piperaceae). Their structures were elucidated by spectroscopic analysis ((1)H, (13)C NMR, and ESI-MS) as follows: guineensine (1), retrofracamide C (2), (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine (3), pipernonaline (4), piperrolein B (5), piperchabamide D (6), pellitorin (7), and dehydropipernonaline (8). Their compounds 3-5, 7, and 8 inhibited potently the direct binding between sICAM-1 and LFA-1 of THP-1 cells in a dose-dependent manner, with IC(50) values of 10.7, 8.8, 13.4, 13.5, and 6.0 microg/mL, respectively.
|
Inhibition of sICAM1/LFA1 interaction-mediated human THP1 cell adhesion at 12.50 ug/mL after 1 hr by ELISA
|
Homo sapiens
|
61.4
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Alkamides from the fruits of Piper longum and Piper nigrum displaying potent cell adhesion inhibition.
Year : 2008
Volume : 18
Issue : 16
First Page : 4544
Last Page : 4546
Authors : Lee SW, Kim YK, Kim K, Lee HS, Choi JH, Lee WS, Jun CD, Park JH, Lee JM, Rho MC.
Abstract : Eight alkamides 1-8 were isolated by bioassay-guided isolation of EtOH extracts of the fruits of Piper longum and Piper nigum (Piperaceae). Their structures were elucidated by spectroscopic analysis ((1)H, (13)C NMR, and ESI-MS) as follows: guineensine (1), retrofracamide C (2), (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine (3), pipernonaline (4), piperrolein B (5), piperchabamide D (6), pellitorin (7), and dehydropipernonaline (8). Their compounds 3-5, 7, and 8 inhibited potently the direct binding between sICAM-1 and LFA-1 of THP-1 cells in a dose-dependent manner, with IC(50) values of 10.7, 8.8, 13.4, 13.5, and 6.0 microg/mL, respectively.
|
Inhibition of sICAM1/LFA1 interaction-mediated human THP1 cell adhesion at 6.25 ug/mL after 1 hr by ELISA
|
Homo sapiens
|
37.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Alkamides from the fruits of Piper longum and Piper nigrum displaying potent cell adhesion inhibition.
Year : 2008
Volume : 18
Issue : 16
First Page : 4544
Last Page : 4546
Authors : Lee SW, Kim YK, Kim K, Lee HS, Choi JH, Lee WS, Jun CD, Park JH, Lee JM, Rho MC.
Abstract : Eight alkamides 1-8 were isolated by bioassay-guided isolation of EtOH extracts of the fruits of Piper longum and Piper nigum (Piperaceae). Their structures were elucidated by spectroscopic analysis ((1)H, (13)C NMR, and ESI-MS) as follows: guineensine (1), retrofracamide C (2), (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine (3), pipernonaline (4), piperrolein B (5), piperchabamide D (6), pellitorin (7), and dehydropipernonaline (8). Their compounds 3-5, 7, and 8 inhibited potently the direct binding between sICAM-1 and LFA-1 of THP-1 cells in a dose-dependent manner, with IC(50) values of 10.7, 8.8, 13.4, 13.5, and 6.0 microg/mL, respectively.
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 1 uM by spectrophotometry in presence of NADPH
|
None
|
-26.98
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of a new class of HMG-CoA reductase inhibitor from Polyalthia longifolia as potential lipid lowering agent.
Year : 2011
Volume : 46
Issue : 10
First Page : 5206
Last Page : 5211
Authors : Sashidhara KV, Singh SP, Srivastava A, Puri A, Chhonker YS, Bhatta RS, Shah P, Siddiqi MI.
Abstract : Bioassay guided fractionation of the ethanolic extract of Polyalthia longifolia var. pendula, led to the discovery of the clerodane diterpene, 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (1), as a new structural class of HMG-CoA reductase inhibitor. Importantly, the in vivo effects of 1 corroborated well with its molecular docking analysis and also with its hamster plasma pharmacokinetics.
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 5 uM by spectrophotometry in presence of NADPH
|
None
|
-36.18
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of a new class of HMG-CoA reductase inhibitor from Polyalthia longifolia as potential lipid lowering agent.
Year : 2011
Volume : 46
Issue : 10
First Page : 5206
Last Page : 5211
Authors : Sashidhara KV, Singh SP, Srivastava A, Puri A, Chhonker YS, Bhatta RS, Shah P, Siddiqi MI.
Abstract : Bioassay guided fractionation of the ethanolic extract of Polyalthia longifolia var. pendula, led to the discovery of the clerodane diterpene, 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (1), as a new structural class of HMG-CoA reductase inhibitor. Importantly, the in vivo effects of 1 corroborated well with its molecular docking analysis and also with its hamster plasma pharmacokinetics.
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 10 uM by spectrophotometry in presence of NADPH
|
None
|
-48.74
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of a new class of HMG-CoA reductase inhibitor from Polyalthia longifolia as potential lipid lowering agent.
Year : 2011
Volume : 46
Issue : 10
First Page : 5206
Last Page : 5211
Authors : Sashidhara KV, Singh SP, Srivastava A, Puri A, Chhonker YS, Bhatta RS, Shah P, Siddiqi MI.
Abstract : Bioassay guided fractionation of the ethanolic extract of Polyalthia longifolia var. pendula, led to the discovery of the clerodane diterpene, 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (1), as a new structural class of HMG-CoA reductase inhibitor. Importantly, the in vivo effects of 1 corroborated well with its molecular docking analysis and also with its hamster plasma pharmacokinetics.
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 20 uM by spectrophotometry in presence of NADPH
|
None
|
-65.32
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of a new class of HMG-CoA reductase inhibitor from Polyalthia longifolia as potential lipid lowering agent.
Year : 2011
Volume : 46
Issue : 10
First Page : 5206
Last Page : 5211
Authors : Sashidhara KV, Singh SP, Srivastava A, Puri A, Chhonker YS, Bhatta RS, Shah P, Siddiqi MI.
Abstract : Bioassay guided fractionation of the ethanolic extract of Polyalthia longifolia var. pendula, led to the discovery of the clerodane diterpene, 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (1), as a new structural class of HMG-CoA reductase inhibitor. Importantly, the in vivo effects of 1 corroborated well with its molecular docking analysis and also with its hamster plasma pharmacokinetics.
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 50 uM by spectrophotometry in presence of NADPH
|
None
|
-80.65
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of a new class of HMG-CoA reductase inhibitor from Polyalthia longifolia as potential lipid lowering agent.
Year : 2011
Volume : 46
Issue : 10
First Page : 5206
Last Page : 5211
Authors : Sashidhara KV, Singh SP, Srivastava A, Puri A, Chhonker YS, Bhatta RS, Shah P, Siddiqi MI.
Abstract : Bioassay guided fractionation of the ethanolic extract of Polyalthia longifolia var. pendula, led to the discovery of the clerodane diterpene, 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (1), as a new structural class of HMG-CoA reductase inhibitor. Importantly, the in vivo effects of 1 corroborated well with its molecular docking analysis and also with its hamster plasma pharmacokinetics.
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 100 uM by spectrophotometry in presence of NADPH
|
None
|
-89.97
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of a new class of HMG-CoA reductase inhibitor from Polyalthia longifolia as potential lipid lowering agent.
Year : 2011
Volume : 46
Issue : 10
First Page : 5206
Last Page : 5211
Authors : Sashidhara KV, Singh SP, Srivastava A, Puri A, Chhonker YS, Bhatta RS, Shah P, Siddiqi MI.
Abstract : Bioassay guided fractionation of the ethanolic extract of Polyalthia longifolia var. pendula, led to the discovery of the clerodane diterpene, 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (1), as a new structural class of HMG-CoA reductase inhibitor. Importantly, the in vivo effects of 1 corroborated well with its molecular docking analysis and also with its hamster plasma pharmacokinetics.
|
DRUGMATRIX: HMG-CoA Reductase enzyme inhibition (substrate: [14C]HMG-CoA)
|
Escherichia coli
|
20.0
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
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 5 uM
|
None
|
27.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and synthesis of novel substituted benzocoumarins as orally active lipid modulating agents.
Year : 2011
Volume : 21
Issue : 22
First Page : 6709
Last Page : 6713
Authors : Sashidhara KV, Kumar M, Modukuri RK, Srivastava A, Puri A.
Abstract : The synthesis of a series of benzocoumarin keto-enamine schiff bases is reported. The novel compounds were evaluated for their antihyperlipidemic activity in the hyperlipidemic hamster model. The compound 11 at a dose of 10 mg/kg body weight significantly lowered the plasma triglyceride levels (TG) by 70%, total cholesterol (TC) by 47%, accompanied by an increase in HDL-C/TC ratio by 80% in hyperlipidemic hamsters to a greater degree than the reference drugs atorvastatin and lovastatin.
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 10 uM
|
None
|
46.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and synthesis of novel substituted benzocoumarins as orally active lipid modulating agents.
Year : 2011
Volume : 21
Issue : 22
First Page : 6709
Last Page : 6713
Authors : Sashidhara KV, Kumar M, Modukuri RK, Srivastava A, Puri A.
Abstract : The synthesis of a series of benzocoumarin keto-enamine schiff bases is reported. The novel compounds were evaluated for their antihyperlipidemic activity in the hyperlipidemic hamster model. The compound 11 at a dose of 10 mg/kg body weight significantly lowered the plasma triglyceride levels (TG) by 70%, total cholesterol (TC) by 47%, accompanied by an increase in HDL-C/TC ratio by 80% in hyperlipidemic hamsters to a greater degree than the reference drugs atorvastatin and lovastatin.
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 25 uM
|
None
|
69.1
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and synthesis of novel substituted benzocoumarins as orally active lipid modulating agents.
Year : 2011
Volume : 21
Issue : 22
First Page : 6709
Last Page : 6713
Authors : Sashidhara KV, Kumar M, Modukuri RK, Srivastava A, Puri A.
Abstract : The synthesis of a series of benzocoumarin keto-enamine schiff bases is reported. The novel compounds were evaluated for their antihyperlipidemic activity in the hyperlipidemic hamster model. The compound 11 at a dose of 10 mg/kg body weight significantly lowered the plasma triglyceride levels (TG) by 70%, total cholesterol (TC) by 47%, accompanied by an increase in HDL-C/TC ratio by 80% in hyperlipidemic hamsters to a greater degree than the reference drugs atorvastatin and lovastatin.
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 50 uM
|
None
|
77.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and synthesis of novel substituted benzocoumarins as orally active lipid modulating agents.
Year : 2011
Volume : 21
Issue : 22
First Page : 6709
Last Page : 6713
Authors : Sashidhara KV, Kumar M, Modukuri RK, Srivastava A, Puri A.
Abstract : The synthesis of a series of benzocoumarin keto-enamine schiff bases is reported. The novel compounds were evaluated for their antihyperlipidemic activity in the hyperlipidemic hamster model. The compound 11 at a dose of 10 mg/kg body weight significantly lowered the plasma triglyceride levels (TG) by 70%, total cholesterol (TC) by 47%, accompanied by an increase in HDL-C/TC ratio by 80% in hyperlipidemic hamsters to a greater degree than the reference drugs atorvastatin and lovastatin.
|
Inhibition of HMG-CoA reductase using HMG-CoA as substrate at 100 uM
|
None
|
84.4
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and synthesis of novel substituted benzocoumarins as orally active lipid modulating agents.
Year : 2011
Volume : 21
Issue : 22
First Page : 6709
Last Page : 6713
Authors : Sashidhara KV, Kumar M, Modukuri RK, Srivastava A, Puri A.
Abstract : The synthesis of a series of benzocoumarin keto-enamine schiff bases is reported. The novel compounds were evaluated for their antihyperlipidemic activity in the hyperlipidemic hamster model. The compound 11 at a dose of 10 mg/kg body weight significantly lowered the plasma triglyceride levels (TG) by 70%, total cholesterol (TC) by 47%, accompanied by an increase in HDL-C/TC ratio by 80% in hyperlipidemic hamsters to a greater degree than the reference drugs atorvastatin and lovastatin.
|
TP_TRANSPORTER: inhibition of Digoxin transepithelial transport (basal to apical) (Digoxin: 5 uM, Lovastatin: 100 uM) in Caco-2 cells
|
None
|
65.0
%
|
|
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.
|
TP_TRANSPORTER: inhibition of Fexofenadine uptake (Fexofenadine: 2 uM, Lovastatin: 100 uM) in Xenopus laevis oocytes
|
Xenopus laevis
|
95.0
%
|
|
Journal : Drug Metab. Dispos.
Title : OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine.
Year : 1999
Volume : 27
Issue : 1
First Page : 866
Last Page : 871
Authors : Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB.
Abstract : Fexofenadine, a nonsedating antihistamine, does not undergo significant metabolic biotransformation. Accordingly, it was hypothesized that uptake and efflux transporters could be importantly involved in the drug's disposition. Utilizing a recombinant vaccinia expression system, members of the organic anion transporting polypeptide family, such as the human organic anion transporting polypeptide (OATP) and rat organic anion transporting polypeptides 1 and 2 (Oatp1 and Oatp2), were found to mediate [(14)C]fexofenadine cellular uptake. On the other hand, the bile acid transporter human sodium taurocholate cotransporting polypeptide (NTCP) and the rat organic cation transporter rOCT1 did not exhibit such activity. P-glycoprotein (P-gp) was identified as a fexofenadine efflux transporter, using the LLC-PK1 cell, a polarized epithelial cell line lacking P-gp, and the derivative cell line (L-MDR1), which overexpresses P-gp. In addition, oral and i.v. administration of [(14)C]fexofenadine to mice lacking mdr1a-encoded P-gp resulted in 5- and 9-fold increases in the drug's plasma and brain levels, respectively, compared with wild-type mice. Also, a number of drug inhibitors of P-gp were found to be effective inhibitors of OATP. Because OATP transporters and P-gp colocalize in organs of importance to drug disposition such as the liver, their activity provides an explanation for the heretofore unknown mechanism(s) responsible for fexofenadine's disposition and suggests potentially similar roles in the disposition of other xenobiotics.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
66.5
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
21.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-17.9
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of HMGR isolated from Mus musculus (mouse) liver assessed as change in NADPH at 8 umol/l by HPLC analysis
|
Mus musculus
|
20.2
%
|
|
Journal : Med Chem Res
Title : Synthesis and antihyperlipidemic efficiency of berberine-based HMG-CoA reductase inhibitor
Year : 2012
Volume : 21
Issue : 7
First Page : 1353
Last Page : 1362
Authors : Ye X, He K, Zhu X, Zhang B, Chen X, Yi J, Li X
|
Inhibition of recombinant HMG-CoA reductase (unknown origin) after 10 mins by spectrophotometric analysis
|
Homo sapiens
|
29.5
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of dual-action inhibitors targeting histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme A reductase for cancer treatment.
Year : 2013
Volume : 56
Issue : 9
First Page : 3645
Last Page : 3655
Authors : Chen JB, Chern TR, Wei TT, Chen CC, Lin JH, Fang JM.
Abstract : A series of dual-action compounds were designed to target histone deacetylase (HDAC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) by having a hydroxamate group essential for chelation with the zinc ion in the active site of HDAC and the key structural elements of statin for binding with both proteins. In our study, the statin hydroxamic acids prepared by a fused strategy are most promising in cancer treatments. These compounds showed potent inhibitory activities against HDACs and HMGR with IC50 values in the nanomolar range. These compounds also effectively reduced the HMGR activity as well as promoted the acetylations of histone and tubulin in cancer cells, but were not toxic to normal cells.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
87.54
%
|
|
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
|
100.71
%
|
|
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.
|
Reductase Activity Assay: The HMGR activity was performed using HMG-CoA reductase assay kit from Sigma-Aldrich with the human recombinant protein or 100 μg total cell lysates from A549 cells. Lovastatin was used as a positive control, and SAHA as a negative control. HMGR activity under defined assay conditions, containing NADPH and HMG-CoA substrate in a final volume of 0.2 mL of 100 mM potassium phosphatate buffer (120 mM KCI, 1 mM EDTA, 5 mM DTT, pH 7.4), were initiated in the presence or absence (control) of test compounds dissolved in dimethylsulfoxide (DMSO). The rates of NADPH consumption were monitored every 20 seconds, for up to 10 minutes, by spectrophotometer at 37° C. and 340 nm.
|
None
|
29.5
nM
|
|
Title : Dual action inhibitors against histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme a reductase
Year : 2015
|
Inhibition of human HMGR catalytic domain at 200 uM using HMG-CoA as substrate measured every 20 secs for 10 mins relative to control
|
Homo sapiens
|
42.0
%
|
|
Journal : J Nat Prod
Title : Lovastatin Analogues from the Soil-Derived Fungus Aspergillus sclerotiorum PSU-RSPG178.
Year : 2016
Volume : 79
Issue : 6
First Page : 1500
Last Page : 1507
Authors : Phainuphong P, Rukachaisirikul V, Saithong S, Phongpaichit S, Bowornwiriyapan K, Muanprasat C, Srimaroeng C, Duangjai A, Sakayaroj J.
Abstract : Three new lovastatin analogues (1, 4, and 5) together with four known lovastatin derivatives, namely, lovastatin (2), α,β-dehydrolovastatin (3), α,β-dehydrodihydromonacolin K (6), and α,β-dehydro-4a,5-dihydromonacolin L (7), were isolated from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178. Their structures were established using spectroscopic evidence. Compound 5 exhibited the most potent activity against HMG-CoA reductase, with an IC50 value of 387 μM. In addition, the present study indicated the direct interaction of compound 5 with HMG-CoA reductase. Compound 5 was considered to be noncytotoxic against noncancerous Vero cells, with an IC50 value of 40.0 μM, whereas compound 2 displayed much stronger activity, with an IC50 value of 2.2 μM.
|
Reductase Activity Assay: The HMGR activity was performed using HMG-CoA reductase assay kit from Sigma-Aldrich with the human recombinant protein or 100 μg total cell lysates from A549 cells. Lovastatin was used as a positive control, and SAHA as a negative control. HMGR activity under defined assay conditions, containing NADPH and HMG-CoA substrate in a final volume of 0.2 mL of 100 mM potassium phosphatate buffer (120 mM KCl, 1 mM EDTA, 5 mM DTT, pH 7.4), were initiated in the presence or absence (control) of test compounds dissolved in dimethylsulfoxide (DMSO). The rates of NADPH consumption were monitored every 20 seconds, for up to 10 minutes, by spectrophotometer at 37° C. and 340 nm.
|
None
|
29.5
nM
|
|
Title : 3,5,N-trihydroxy-alkanamide and derivatives: method for making same and use thereof
Year : 2016
|
Inhibition of HMG-CoA reductase (unknown origin) using [14C]-HMG-CoA as substrate after 5 mins in presence of NADPH
|
Homo sapiens
|
2.2
nM
|
|
Journal : J Med Chem
Title : Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.
Year : 2018
Volume : 61
Issue : 6
First Page : 2166
Last Page : 2210
Authors : Talele TT.
Abstract : The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
9.76
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
0.96
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
12.43
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
18.99
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
19.83
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
17.1
%
|
|
|
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
|
-5.68
%
|
|
|
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
|
19.66
%
|
|
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.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
6.32
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.696
%
|
|
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.
|
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
|
0.61
%
|
|
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
|
0.65
%
|
|
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
|
0.65
%
|
|
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
|
0.61
%
|
|
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.
