|
Antagonist activity against Androgen receptor
|
Homo sapiens
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives as progesterone receptor modulators.
Year : 2003
Volume : 13
Issue : 12
First Page : 2071
Last Page : 2074
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives were synthesized and tested in biological assays to evaluate scope and limitations of the nonsteroidal SPRM pharmacophore (3). A number of orally available highly potent nonsteroidal modulators were identified by modification of the substituents at 5-methylidene position.
|
Antagonistic activity was determined in Human androgen receptor(hAR) of CV-1 cells in cotransfection assay.
|
None
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 3
First Page : 291
Last Page : 302
Authors : Zhi L, Tegley CM, Kallel EA, Marschke KB, Mais DE, Gottardis MM, Jones TK.
Abstract : The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.
|
Inhibition of human androgen receptor at 10e-12 to 10e-5 M
|
Homo sapiens
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : 5-benzylidene-1,2-dihydrochromeno[3,4-f]quinolines as selective progesterone receptor modulators.
Year : 2003
Volume : 46
Issue : 19
First Page : 4104
Last Page : 4112
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Motamedi M, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.
|
Inhibitory activity against Androgen receptor
|
Mus musculus
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel 6-aryl-1,4-dihydrobenzo[d]oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists.
Year : 2003
Volume : 13
Issue : 7
First Page : 1313
Last Page : 1316
Authors : Zhang P, Terefenko EA, Fensome A, Wrobel J, Winneker R, Zhang Z.
Abstract : The functional activity of 6-aryl benzoxazinone-based progesterone (PR) antagonists changed to PR agonism when the 2-carbonyl group was replaced by a 2-thiocarbonyl moiety. Based on this finding novel 6-aryl benzoxazine-2-thiones were synthesized and evaluated as PR agonists in various in vitro and in vivo assays. Several analogues had sub-nanomolar in vitro potency and showed excellent oral activities in rats. Compounds 15 and 29 had similar potencies to medroxyprogesterone acetate (MPA) in the in vitro T47D alkaline phosphatase assay and in vivo rat decidualization model. In contrast to MPA, 29 was highly selective (>500-fold) for PR over glucocorticoid and androgen receptors.
|
Inhibitory activity against human Androgen receptor
|
Homo sapiens
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists based on cyclocymopol monomethyl ether.
Year : 1996
Volume : 39
Issue : 9
First Page : 1778
Last Page : 1789
Authors : Hamann LG, Farmer LJ, Johnson MG, Bender SL, Mais DE, Wang MW, Crombie D, Goldman ME, Jones TK.
Abstract : A novel class of nonsteroidal progesterone receptor antagonists has been synthesized and was shown to exhibit moderate binding affinity for hPR-A, the ability to inhibit the transcriptional activity of human progesterone receptor (hPR) in cell-based assays, and anti-progestational activity in a murine model. Cyclocymopol monomethyl ether, a component of the marine alga Cymopolia barbata was weakly active in random screening against PR. Investigations into the SAR surrounding the core of this natural product lead structure resulted in improved in vitro activity. In contrast to the cross-reactivity profiles observed with known steroidal antiprogestins, compounds of the general structural class described display a high degree of selectivity for the progesterone receptor and no functional activity on the glucocorticoid receptor.
|
Inhibitory activity against Androgen receptor
|
Mus musculus
|
46.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel 6-aryl-1,4-dihydrobenzo[d]oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists.
Year : 2003
Volume : 13
Issue : 7
First Page : 1313
Last Page : 1316
Authors : Zhang P, Terefenko EA, Fensome A, Wrobel J, Winneker R, Zhang Z.
Abstract : The functional activity of 6-aryl benzoxazinone-based progesterone (PR) antagonists changed to PR agonism when the 2-carbonyl group was replaced by a 2-thiocarbonyl moiety. Based on this finding novel 6-aryl benzoxazine-2-thiones were synthesized and evaluated as PR agonists in various in vitro and in vivo assays. Several analogues had sub-nanomolar in vitro potency and showed excellent oral activities in rats. Compounds 15 and 29 had similar potencies to medroxyprogesterone acetate (MPA) in the in vitro T47D alkaline phosphatase assay and in vivo rat decidualization model. In contrast to MPA, 29 was highly selective (>500-fold) for PR over glucocorticoid and androgen receptors.
|
Binding affinity for human Androgen receptor
|
Homo sapiens
|
8.5
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists based on cyclocymopol monomethyl ether.
Year : 1996
Volume : 39
Issue : 9
First Page : 1778
Last Page : 1789
Authors : Hamann LG, Farmer LJ, Johnson MG, Bender SL, Mais DE, Wang MW, Crombie D, Goldman ME, Jones TK.
Abstract : A novel class of nonsteroidal progesterone receptor antagonists has been synthesized and was shown to exhibit moderate binding affinity for hPR-A, the ability to inhibit the transcriptional activity of human progesterone receptor (hPR) in cell-based assays, and anti-progestational activity in a murine model. Cyclocymopol monomethyl ether, a component of the marine alga Cymopolia barbata was weakly active in random screening against PR. Investigations into the SAR surrounding the core of this natural product lead structure resulted in improved in vitro activity. In contrast to the cross-reactivity profiles observed with known steroidal antiprogestins, compounds of the general structural class described display a high degree of selectivity for the progesterone receptor and no functional activity on the glucocorticoid receptor.
|
Displacement of DHT from human androgen receptor
|
Homo sapiens
|
8.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-Alkyl 1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal progesterone receptor modulators.
Year : 1998
Volume : 8
Issue : 23
First Page : 3365
Last Page : 3370
Authors : Zhi L, Tegley CM, Edwards JP, West SJ, Marschke KB, Gottardis MM, Mais DE, Jones TK.
Abstract : A series of nonsteroidal human progesterone receptor (hPR) agonists, 5-alkyl 1,2-dihydrochromeno[3,4-f]quinolines, was synthesized and evaluated in cotransfection and competitive receptor binding assays. The 5-alkyl substitution was shown to be responsible for the agonist activity and substitution at C9 dramatically enhanced the potency. A number of analogues in this series showed activities similar to or better than progesterone in the cotransfection and binding assays and analogue 15 exhibited similar in vivo activity as medroxyprogesterone acetate (MPA) in murine uterine wet weight/mammary gland morphology assays.
|
Displacement of DHT from human androgen receptor expressed in baculovirus SF-12 cells
|
Homo sapiens
|
8.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-benzylidene-1,2-dihydrochromeno[3,4-f]quinolines as selective progesterone receptor modulators.
Year : 2003
Volume : 46
Issue : 19
First Page : 4104
Last Page : 4112
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Motamedi M, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.
|
Binding affinity against human androgen receptor
|
None
|
8.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 22
First Page : 4354
Last Page : 4359
Authors : Tegley CM, Zhi L, Marschke KB, Gottardis MM, Yang Q, Jones TK.
Abstract : A novel series of nonsteroidal progestins, 5-benzylidene-1, 2-dihydrochromeno[3,4-f]quinolines (2), was discovered, and a preliminary structure-activity relationship study around the 5-benzylidene ring generated several potent human progesterone receptor agonists (compounds 8, 16). These new progestins showed biological activities (EC50 = 5.7 and 7.6 nM) similar to progesterone (EC50 = 2.9 nM) in the cotransfection assay with high efficacy (132% and 166%) and binding affinity (Ki = 0.66 and 0.83 nM) similar to medroxyprogesterone acetate (MPA) (Ki = 0.34 nM). A representative analogue, 8, demonstrated similar oral potency to MPA in the uterine wet weight/mammary gland morphology assay in ovariectomized rats.
|
Binding affinity against baculovirus expressed human androgen receptor (hAR)
|
None
|
8.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2,3,4-tetrahydrochromeno[3,4-f]quinolin-3-ones as a novel class of nonsteroidal progesterone receptor agonists: effect of A-ring modification.
Year : 1999
Volume : 42
Issue : 8
First Page : 1466
Last Page : 1472
Authors : Zhi L, Tegley CM, Marschke KB, Mais DE, Jones TK.
Abstract : Optimization of the 1,2-dihydroquinoline A-ring of a nonsteroidal human progesterone receptor (hPR) agonist pharmacophore (1) was performed by using the cotransfection and receptor binding assays as guides. The 3-keto group was discovered to regain the potent agonist activity which was lost upon removal of the 3,4-olefin, and it led to a novel hPR agonist series, 5-aryl-1,2,3,4-tetrahydrochromeno[3, 4-f]quinolin-3-ones. The new progestins demonstrated potent hPR agonist activity in the cotransfection assay and high binding affinity similar to progesterone. T47D human breast cancer cell line was employed for further characterization of the new progestins and a number of reference analogues. It was found that the new 3-keto analogues showed full agonist activity in the T47D assay, while the reference compounds from other related nonsteroidal hPR agonist series exhibited only partial agonist activity.
|
Binding affinity was determined on Human androgen receptor (hAR) using progesterone as radioligand.
|
None
|
8.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 3
First Page : 291
Last Page : 302
Authors : Zhi L, Tegley CM, Kallel EA, Marschke KB, Mais DE, Gottardis MM, Jones TK.
Abstract : The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.
|
Effective concentration (EC50) against human progesterone receptor expressed in CV-1 cell
|
Homo sapiens
|
2.9
nM
|
|
Journal : J. Med. Chem.
Title : 5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 22
First Page : 4354
Last Page : 4359
Authors : Tegley CM, Zhi L, Marschke KB, Gottardis MM, Yang Q, Jones TK.
Abstract : A novel series of nonsteroidal progestins, 5-benzylidene-1, 2-dihydrochromeno[3,4-f]quinolines (2), was discovered, and a preliminary structure-activity relationship study around the 5-benzylidene ring generated several potent human progesterone receptor agonists (compounds 8, 16). These new progestins showed biological activities (EC50 = 5.7 and 7.6 nM) similar to progesterone (EC50 = 2.9 nM) in the cotransfection assay with high efficacy (132% and 166%) and binding affinity (Ki = 0.66 and 0.83 nM) similar to medroxyprogesterone acetate (MPA) (Ki = 0.34 nM). A representative analogue, 8, demonstrated similar oral potency to MPA in the uterine wet weight/mammary gland morphology assay in ovariectomized rats.
|
Inhibitory activity (IC50) against human androgen receptor expressed in CV-1 cells
|
Homo sapiens
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : 5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 22
First Page : 4354
Last Page : 4359
Authors : Tegley CM, Zhi L, Marschke KB, Gottardis MM, Yang Q, Jones TK.
Abstract : A novel series of nonsteroidal progestins, 5-benzylidene-1, 2-dihydrochromeno[3,4-f]quinolines (2), was discovered, and a preliminary structure-activity relationship study around the 5-benzylidene ring generated several potent human progesterone receptor agonists (compounds 8, 16). These new progestins showed biological activities (EC50 = 5.7 and 7.6 nM) similar to progesterone (EC50 = 2.9 nM) in the cotransfection assay with high efficacy (132% and 166%) and binding affinity (Ki = 0.66 and 0.83 nM) similar to medroxyprogesterone acetate (MPA) (Ki = 0.34 nM). A representative analogue, 8, demonstrated similar oral potency to MPA in the uterine wet weight/mammary gland morphology assay in ovariectomized rats.
|
Inhibitory activity (IC50) against human mineralocorticoid receptor expressed in CV-1 cells
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : 5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 22
First Page : 4354
Last Page : 4359
Authors : Tegley CM, Zhi L, Marschke KB, Gottardis MM, Yang Q, Jones TK.
Abstract : A novel series of nonsteroidal progestins, 5-benzylidene-1, 2-dihydrochromeno[3,4-f]quinolines (2), was discovered, and a preliminary structure-activity relationship study around the 5-benzylidene ring generated several potent human progesterone receptor agonists (compounds 8, 16). These new progestins showed biological activities (EC50 = 5.7 and 7.6 nM) similar to progesterone (EC50 = 2.9 nM) in the cotransfection assay with high efficacy (132% and 166%) and binding affinity (Ki = 0.66 and 0.83 nM) similar to medroxyprogesterone acetate (MPA) (Ki = 0.34 nM). A representative analogue, 8, demonstrated similar oral potency to MPA in the uterine wet weight/mammary gland morphology assay in ovariectomized rats.
|
Inhibition of 10e-9 M aldosterone activity in CV-1 cells expressing mineralocorticoid receptor
|
Homo sapiens
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : New steroidal diazo ketones as potential photoaffinity labeling reagents for the mineralocorticoid receptor: synthesis and biological activities.
Year : 1996
Volume : 39
Issue : 14
First Page : 2860
Last Page : 2864
Authors : Davioud E, Fagart J, Souque A, Rafestin-Oblin ME, Marquet A.
Abstract : Three diazo ketones in the progesterone series were synthesized as potential photoaffinity reagents. The diazo ketone group was introduced at the C17 (21-diazopregn-4-ene-3,20-dione, 1) or C13 (18-(diazomethyl)-20-hydroxypregn-4-ene-3,18-dione, 2, 18-(diazomethyl)pregn-4-ene-3, 18,20-trione, 3) position of the pregnene skeleton. Whereas compound 1 could be easily obtained from the corresponding acid chloride, preparation of 2 and 3 required a less straightforward route involving reaction of tosyl azide on the formyl derivative of methyl ketone 5. The affinity of the diazo ketones for the human mineralocorticoid receptor (hMR), expressed in Sf9 insect cells using the Baculovirus system, was estimated by competition experiments using [3H]aldosterone as specific ligand. The affinity of 1 for hMR was almost identical with that of aldosterone. The affinities of 2 and 3 were 1, order of magnitude lower than that of aldosterone. The mineralocorticoid activity of the diazo ketones was measured in cis-trans cotransfection assays in CV-1 cells with the mouse mammary tumor virus as DNA target sequence. Compound 1 exhibits an agonist activity (ED50 = 6 x 10(-9) M) with no antagonist activity. In contrast 2 and 3 behave as antagonists, displaying an IC50 of approximately 10(-6) M whether the substituent at the C20 position is a hydroxy (2) or an oxo (3) group.
|
Binding affinity to human CBG receptor (corticosteroid-binding globulins)
|
None
|
41.69
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.
|
Equilibrium dissociation constant for rat uterine estrogen receptor binding [3H]estradiol
|
Rattus norvegicus
|
3.9
nM
|
|
Journal : J. Med. Chem.
Title : Steroids. 2. Synthesis of C-18 functionalized steroids via the Smith-Hughes route.
Year : 1984
Volume : 27
Issue : 9
First Page : 1131
Last Page : 1137
Authors : Pillai KM, Murray WV, Shooshani I, Williams DL, Gordon D, Wang SY, Johnson F.
Abstract : The total synthesis of a series of racemic C-18 functionalized steroids was carried out in a search for novel estrogen-and/or progestin-receptor agonists or antagonists. The target compound 3,18-dihydroxyestra-1,3,5(10)-triene (2), 13-(2-oxopropyl)gona-4-en-3-one (3), 13-(1-hydroxy-1-prop-2-ynyl)gona-4-en-3-one (4a and 4b) and 13-(1-acetoxy-2-oxo-1-propyl)gona-4-en-3-one (5) are position isomers of the highly biologically active estradiol, progesterone, norethindrone, and 17-acetoxyprogesterone, respectively. Nevertheless the synthetic C-18 functionalized steroids 3-5 showed little activity in the Clauberg and anti-Clauberg assays. Compound 2 showed no antagonism in the postcoital assay despite the fact that it exhibited weak but measurable in vitro receptor-binding activity.
|
Binding affinity was determined for human glucocorticoid receptor(hGR).
|
None
|
30.5
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists based on cyclocymopol monomethyl ether.
Year : 1996
Volume : 39
Issue : 9
First Page : 1778
Last Page : 1789
Authors : Hamann LG, Farmer LJ, Johnson MG, Bender SL, Mais DE, Wang MW, Crombie D, Goldman ME, Jones TK.
Abstract : A novel class of nonsteroidal progesterone receptor antagonists has been synthesized and was shown to exhibit moderate binding affinity for hPR-A, the ability to inhibit the transcriptional activity of human progesterone receptor (hPR) in cell-based assays, and anti-progestational activity in a murine model. Cyclocymopol monomethyl ether, a component of the marine alga Cymopolia barbata was weakly active in random screening against PR. Investigations into the SAR surrounding the core of this natural product lead structure resulted in improved in vitro activity. In contrast to the cross-reactivity profiles observed with known steroidal antiprogestins, compounds of the general structural class described display a high degree of selectivity for the progesterone receptor and no functional activity on the glucocorticoid receptor.
|
Displacement of Dexamethasone from human glucocorticoid receptor
|
Homo sapiens
|
30.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-Alkyl 1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal progesterone receptor modulators.
Year : 1998
Volume : 8
Issue : 23
First Page : 3365
Last Page : 3370
Authors : Zhi L, Tegley CM, Edwards JP, West SJ, Marschke KB, Gottardis MM, Mais DE, Jones TK.
Abstract : A series of nonsteroidal human progesterone receptor (hPR) agonists, 5-alkyl 1,2-dihydrochromeno[3,4-f]quinolines, was synthesized and evaluated in cotransfection and competitive receptor binding assays. The 5-alkyl substitution was shown to be responsible for the agonist activity and substitution at C9 dramatically enhanced the potency. A number of analogues in this series showed activities similar to or better than progesterone in the cotransfection and binding assays and analogue 15 exhibited similar in vivo activity as medroxyprogesterone acetate (MPA) in murine uterine wet weight/mammary gland morphology assays.
|
Displacement of Dexamethasone from human glucocorticoid receptor expressed in baculovirus SF-12 cells
|
Homo sapiens
|
30.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-benzylidene-1,2-dihydrochromeno[3,4-f]quinolines as selective progesterone receptor modulators.
Year : 2003
Volume : 46
Issue : 19
First Page : 4104
Last Page : 4112
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Motamedi M, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.
|
Binding affinity against human glucocorticoid receptor expressed in SF-12 cells
|
Homo sapiens
|
30.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 22
First Page : 4354
Last Page : 4359
Authors : Tegley CM, Zhi L, Marschke KB, Gottardis MM, Yang Q, Jones TK.
Abstract : A novel series of nonsteroidal progestins, 5-benzylidene-1, 2-dihydrochromeno[3,4-f]quinolines (2), was discovered, and a preliminary structure-activity relationship study around the 5-benzylidene ring generated several potent human progesterone receptor agonists (compounds 8, 16). These new progestins showed biological activities (EC50 = 5.7 and 7.6 nM) similar to progesterone (EC50 = 2.9 nM) in the cotransfection assay with high efficacy (132% and 166%) and binding affinity (Ki = 0.66 and 0.83 nM) similar to medroxyprogesterone acetate (MPA) (Ki = 0.34 nM). A representative analogue, 8, demonstrated similar oral potency to MPA in the uterine wet weight/mammary gland morphology assay in ovariectomized rats.
|
Binding affinity against baculovirus expressed human glucocorticoid receptor (hGR)
|
None
|
30.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2,3,4-tetrahydrochromeno[3,4-f]quinolin-3-ones as a novel class of nonsteroidal progesterone receptor agonists: effect of A-ring modification.
Year : 1999
Volume : 42
Issue : 8
First Page : 1466
Last Page : 1472
Authors : Zhi L, Tegley CM, Marschke KB, Mais DE, Jones TK.
Abstract : Optimization of the 1,2-dihydroquinoline A-ring of a nonsteroidal human progesterone receptor (hPR) agonist pharmacophore (1) was performed by using the cotransfection and receptor binding assays as guides. The 3-keto group was discovered to regain the potent agonist activity which was lost upon removal of the 3,4-olefin, and it led to a novel hPR agonist series, 5-aryl-1,2,3,4-tetrahydrochromeno[3, 4-f]quinolin-3-ones. The new progestins demonstrated potent hPR agonist activity in the cotransfection assay and high binding affinity similar to progesterone. T47D human breast cancer cell line was employed for further characterization of the new progestins and a number of reference analogues. It was found that the new 3-keto analogues showed full agonist activity in the T47D assay, while the reference compounds from other related nonsteroidal hPR agonist series exhibited only partial agonist activity.
|
Binding affinity was determined on Human glucocorticoid receptor (hAR) using progesterone as radioligand.
|
None
|
30.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 3
First Page : 291
Last Page : 302
Authors : Zhi L, Tegley CM, Kallel EA, Marschke KB, Mais DE, Gottardis MM, Jones TK.
Abstract : The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.
|
Antagonist activity at mineralocorticoid receptor (hMR)
|
Homo sapiens
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives as progesterone receptor modulators.
Year : 2003
Volume : 13
Issue : 12
First Page : 2071
Last Page : 2074
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives were synthesized and tested in biological assays to evaluate scope and limitations of the nonsteroidal SPRM pharmacophore (3). A number of orally available highly potent nonsteroidal modulators were identified by modification of the substituents at 5-methylidene position.
|
Antagonistic activity was determined in Human mineralocorticoid receptor(hMR) of CV-1 cells in cotransfection assay.
|
None
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 3
First Page : 291
Last Page : 302
Authors : Zhi L, Tegley CM, Kallel EA, Marschke KB, Mais DE, Gottardis MM, Jones TK.
Abstract : The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.
|
Inhibitory activity against human Mineralocorticoid receptor
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : 5-benzylidene-1,2-dihydrochromeno[3,4-f]quinolines as selective progesterone receptor modulators.
Year : 2003
Volume : 46
Issue : 19
First Page : 4104
Last Page : 4112
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Motamedi M, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.
|
Inhibitory activity against human mineralocorticoid receptor (hMR)
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists based on cyclocymopol monomethyl ether.
Year : 1996
Volume : 39
Issue : 9
First Page : 1778
Last Page : 1789
Authors : Hamann LG, Farmer LJ, Johnson MG, Bender SL, Mais DE, Wang MW, Crombie D, Goldman ME, Jones TK.
Abstract : A novel class of nonsteroidal progesterone receptor antagonists has been synthesized and was shown to exhibit moderate binding affinity for hPR-A, the ability to inhibit the transcriptional activity of human progesterone receptor (hPR) in cell-based assays, and anti-progestational activity in a murine model. Cyclocymopol monomethyl ether, a component of the marine alga Cymopolia barbata was weakly active in random screening against PR. Investigations into the SAR surrounding the core of this natural product lead structure resulted in improved in vitro activity. In contrast to the cross-reactivity profiles observed with known steroidal antiprogestins, compounds of the general structural class described display a high degree of selectivity for the progesterone receptor and no functional activity on the glucocorticoid receptor.
|
Affinity for recombinant Mineralocorticoid receptor
|
Homo sapiens
|
0.39
nM
|
|
Journal : J. Med. Chem.
Title : New steroidal diazo ketones as potential photoaffinity labeling reagents for the mineralocorticoid receptor: synthesis and biological activities.
Year : 1996
Volume : 39
Issue : 14
First Page : 2860
Last Page : 2864
Authors : Davioud E, Fagart J, Souque A, Rafestin-Oblin ME, Marquet A.
Abstract : Three diazo ketones in the progesterone series were synthesized as potential photoaffinity reagents. The diazo ketone group was introduced at the C17 (21-diazopregn-4-ene-3,20-dione, 1) or C13 (18-(diazomethyl)-20-hydroxypregn-4-ene-3,18-dione, 2, 18-(diazomethyl)pregn-4-ene-3, 18,20-trione, 3) position of the pregnene skeleton. Whereas compound 1 could be easily obtained from the corresponding acid chloride, preparation of 2 and 3 required a less straightforward route involving reaction of tosyl azide on the formyl derivative of methyl ketone 5. The affinity of the diazo ketones for the human mineralocorticoid receptor (hMR), expressed in Sf9 insect cells using the Baculovirus system, was estimated by competition experiments using [3H]aldosterone as specific ligand. The affinity of 1 for hMR was almost identical with that of aldosterone. The affinities of 2 and 3 were 1, order of magnitude lower than that of aldosterone. The mineralocorticoid activity of the diazo ketones was measured in cis-trans cotransfection assays in CV-1 cells with the mouse mammary tumor virus as DNA target sequence. Compound 1 exhibits an agonist activity (ED50 = 6 x 10(-9) M) with no antagonist activity. In contrast 2 and 3 behave as antagonists, displaying an IC50 of approximately 10(-6) M whether the substituent at the C20 position is a hydroxy (2) or an oxo (3) group.
|
Agonistic activity against human progesterone receptor in CV-1 cells
|
None
|
2.9
nM
|
|
Journal : J. Med. Chem.
Title : 5-benzylidene-1,2-dihydrochromeno[3,4-f]quinolines as selective progesterone receptor modulators.
Year : 2003
Volume : 46
Issue : 19
First Page : 4104
Last Page : 4112
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Motamedi M, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.
|
Agonistic activity against human progesterone receptor in T47D breast cancer cells
|
None
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : 5-benzylidene-1,2-dihydrochromeno[3,4-f]quinolines as selective progesterone receptor modulators.
Year : 2003
Volume : 46
Issue : 19
First Page : 4104
Last Page : 4112
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Motamedi M, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.
|
Agonist activity was determined against hPR (human progesterone receptor) compared to that of progesterone (100%)
|
None
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-Alkyl 1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal progesterone receptor modulators.
Year : 1998
Volume : 8
Issue : 23
First Page : 3365
Last Page : 3370
Authors : Zhi L, Tegley CM, Edwards JP, West SJ, Marschke KB, Gottardis MM, Mais DE, Jones TK.
Abstract : A series of nonsteroidal human progesterone receptor (hPR) agonists, 5-alkyl 1,2-dihydrochromeno[3,4-f]quinolines, was synthesized and evaluated in cotransfection and competitive receptor binding assays. The 5-alkyl substitution was shown to be responsible for the agonist activity and substitution at C9 dramatically enhanced the potency. A number of analogues in this series showed activities similar to or better than progesterone in the cotransfection and binding assays and analogue 15 exhibited similar in vivo activity as medroxyprogesterone acetate (MPA) in murine uterine wet weight/mammary gland morphology assays.
|
Agonistic activity to the human progesterone receptor (hPR)assayed in CV-1 cells in cotransfection assay.
|
None
|
2.9
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 3
First Page : 291
Last Page : 302
Authors : Zhi L, Tegley CM, Kallel EA, Marschke KB, Mais DE, Gottardis MM, Jones TK.
Abstract : The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.
|
Agonistic activity was measured for modulation of hPR-B (human progesterone receptor) in co-transfected CV-1 cells.
|
Homo sapiens
|
2.89
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines as potent, orally active, nonsteroidal progesterone receptor agonists: the effect of D-ring substituents.
Year : 1998
Volume : 41
Issue : 3
First Page : 303
Last Page : 310
Authors : Edwards JP, West SJ, Marschke KB, Mais DE, Gottardis MM, Jones TK.
Abstract : Several 5-(4-chlorophenyl)-1,2-dihydro-5H-chromeno[3,4-f]quinolines were prepared to determine the effects of substitution at C(8) and C(9) on the progestational activity of this pharmacophore. In combination with a halogen (F or Cl) at C(9), replacement of the C(5) aryl group with variously substituted aryl groups resulted in optimization of the progestational activity, affording compounds with in vitro activity greater than that of progesterone as measured by a cotransfection assay using human progesterone receptor subtype-B (hPR-B). Binding affinities (Ki) to hPR-A were subnanomolar in many cases. These in vitro effects were verified in vivo using a rodent model. Compound 10 (LG120794, 9-chloro-5-(4-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno++ +[3,4-f] quinoline) was more potent than medroxyprogesterone acetate at counterpoising the effects of estradiol benzoate in the uterine wet weight assay using immature rats.
|
Compound was tested for agonistic activity by cotransfection assay against human Progesterone receptor in CV-1 cells
|
None
|
2.9
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2,3,4-tetrahydrochromeno[3,4-f]quinolin-3-ones as a novel class of nonsteroidal progesterone receptor agonists: effect of A-ring modification.
Year : 1999
Volume : 42
Issue : 8
First Page : 1466
Last Page : 1472
Authors : Zhi L, Tegley CM, Marschke KB, Mais DE, Jones TK.
Abstract : Optimization of the 1,2-dihydroquinoline A-ring of a nonsteroidal human progesterone receptor (hPR) agonist pharmacophore (1) was performed by using the cotransfection and receptor binding assays as guides. The 3-keto group was discovered to regain the potent agonist activity which was lost upon removal of the 3,4-olefin, and it led to a novel hPR agonist series, 5-aryl-1,2,3,4-tetrahydrochromeno[3, 4-f]quinolin-3-ones. The new progestins demonstrated potent hPR agonist activity in the cotransfection assay and high binding affinity similar to progesterone. T47D human breast cancer cell line was employed for further characterization of the new progestins and a number of reference analogues. It was found that the new 3-keto analogues showed full agonist activity in the T47D assay, while the reference compounds from other related nonsteroidal hPR agonist series exhibited only partial agonist activity.
|
Agonistic activity by cotransfection assay against human Progesterone receptor in T47D cells
|
None
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2,3,4-tetrahydrochromeno[3,4-f]quinolin-3-ones as a novel class of nonsteroidal progesterone receptor agonists: effect of A-ring modification.
Year : 1999
Volume : 42
Issue : 8
First Page : 1466
Last Page : 1472
Authors : Zhi L, Tegley CM, Marschke KB, Mais DE, Jones TK.
Abstract : Optimization of the 1,2-dihydroquinoline A-ring of a nonsteroidal human progesterone receptor (hPR) agonist pharmacophore (1) was performed by using the cotransfection and receptor binding assays as guides. The 3-keto group was discovered to regain the potent agonist activity which was lost upon removal of the 3,4-olefin, and it led to a novel hPR agonist series, 5-aryl-1,2,3,4-tetrahydrochromeno[3, 4-f]quinolin-3-ones. The new progestins demonstrated potent hPR agonist activity in the cotransfection assay and high binding affinity similar to progesterone. T47D human breast cancer cell line was employed for further characterization of the new progestins and a number of reference analogues. It was found that the new 3-keto analogues showed full agonist activity in the T47D assay, while the reference compounds from other related nonsteroidal hPR agonist series exhibited only partial agonist activity.
|
Effective concentration for agonist activity towards human progesterone receptor (hPR) using the cotransfection assay in CV-1 cells
|
None
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives as progesterone receptor modulators.
Year : 2003
Volume : 13
Issue : 12
First Page : 2071
Last Page : 2074
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives were synthesized and tested in biological assays to evaluate scope and limitations of the nonsteroidal SPRM pharmacophore (3). A number of orally available highly potent nonsteroidal modulators were identified by modification of the substituents at 5-methylidene position.
|
Effective concentration against PR (progesterone receptor)
|
Homo sapiens
|
0.92
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel 6-aryl-1,4-dihydrobenzo[d]oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists.
Year : 2003
Volume : 13
Issue : 7
First Page : 1313
Last Page : 1316
Authors : Zhang P, Terefenko EA, Fensome A, Wrobel J, Winneker R, Zhang Z.
Abstract : The functional activity of 6-aryl benzoxazinone-based progesterone (PR) antagonists changed to PR agonism when the 2-carbonyl group was replaced by a 2-thiocarbonyl moiety. Based on this finding novel 6-aryl benzoxazine-2-thiones were synthesized and evaluated as PR agonists in various in vitro and in vivo assays. Several analogues had sub-nanomolar in vitro potency and showed excellent oral activities in rats. Compounds 15 and 29 had similar potencies to medroxyprogesterone acetate (MPA) in the in vitro T47D alkaline phosphatase assay and in vivo rat decidualization model. In contrast to MPA, 29 was highly selective (>500-fold) for PR over glucocorticoid and androgen receptors.
|
Agonistic activity against progesterone receptor in alkaline phosphatase assay using human T47D breast carcinoma cell line
|
None
|
0.92
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines.
Year : 2002
Volume : 12
Issue : 5
First Page : 787
Last Page : 790
Authors : Zhang P, Terefenko EA, Fensome A, Zhang Z, Zhu Y, Cohen J, Winneker R, Wrobel J, Yardley J.
Abstract : Novel 6-aryl benzoxazines were prepared and examined as progesterone receptor (PR) modulators. In contrast to the structurally related 6-aryl dihydroquinoline PR antagonists, the 6-aryl benzoxazines were potent PR agonists. Compounds 4e, 5b, and 6a with the 2,4,4-trimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazine core were the most potent PR agonists in the series with sub-nanomolar activities (EC(50) 0.20-0.35nM). Compound 6a was more potent than progesterone (P4) in the in vivo decidualization assay in an ovariectomized female rat model by subcutaneous administration with an ED(50) of 1.5mg/kg (vs 5.62mg/kg for P4).
|
Human progesterone receptor (hPR) agonist activity in T47D human breast cancer cell line
|
None
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nonsteroidal progesterone receptor antagonists based on 6-thiophenehydroquinolines.
Year : 2000
Volume : 10
Issue : 5
First Page : 415
Last Page : 418
Authors : Zhi L, Tegley CM, Pio B, West SJ, Marschke KB, Mais DE, Jones TK.
Abstract : Synthesis and biological evaluation of 6-thiophene 1,2-dihydro or 1,2,3,4-tetrahydroquinoline derivatives resulted in a number of potent nonsteroidal antiprogestins.
|
Human progesterone receptor (hPR) agonist activity expressed in CV-1 cells
|
Homo sapiens
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nonsteroidal progesterone receptor antagonists based on 6-thiophenehydroquinolines.
Year : 2000
Volume : 10
Issue : 5
First Page : 415
Last Page : 418
Authors : Zhi L, Tegley CM, Pio B, West SJ, Marschke KB, Mais DE, Jones TK.
Abstract : Synthesis and biological evaluation of 6-thiophene 1,2-dihydro or 1,2,3,4-tetrahydroquinoline derivatives resulted in a number of potent nonsteroidal antiprogestins.
|
Binding affinity against Progesterone receptor in human TE85 osteosarcoma cells was determined using (Z)-[125I]-17-alpha-(2-iodovinyl)-19-nor-testosterone as radioligand
|
None
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Nonsteroidal progesterone receptor ligands. 2. High-affinity ligands with selectivity for bone cell progesterone receptors.
Year : 1995
Volume : 38
Issue : 25
First Page : 4880
Last Page : 4884
Authors : Combs DW, Reese K, Cornelius LA, Gunnet JW, Cryan EV, Granger KS, Jordan JJ, Demarest KT.
Abstract : A novel series of nonsteroidal heterocycles was discovered which display cell-type selective, high-affinity (nanomolar) binding to the progesterone receptors from TE85 osteosarcoma cells but > 1 microM binding affinity to the progesterone receptors from T47D and ZR75 human breast carcinoma cells. Structure-activity relationships were developed for a set of these compounds, and a representative analog 1-(3,4-dichlorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine++ + (1i, RWJ 25333) was chosen for further evaluation. RWJ 25333 stimulated the in vitro proliferation of human osteoblast-like cells but not human breast cells.
|
Binding affinity towards human progesterone receptor
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Nonsteroidal progesterone receptor ligands. 1. 3-Aryl-1-benzoyl-1,4,5,6-tetrahydropyridazines.
Year : 1995
Volume : 38
Issue : 25
First Page : 4878
Last Page : 4879
Authors : Combs DW, Reese K, Phillips A.
|
Binding affinity for Progesterone receptor (PR) in human T47D breast carcinoma cells
|
Homo sapiens
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines.
Year : 2002
Volume : 12
Issue : 5
First Page : 787
Last Page : 790
Authors : Zhang P, Terefenko EA, Fensome A, Zhang Z, Zhu Y, Cohen J, Winneker R, Wrobel J, Yardley J.
Abstract : Novel 6-aryl benzoxazines were prepared and examined as progesterone receptor (PR) modulators. In contrast to the structurally related 6-aryl dihydroquinoline PR antagonists, the 6-aryl benzoxazines were potent PR agonists. Compounds 4e, 5b, and 6a with the 2,4,4-trimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazine core were the most potent PR agonists in the series with sub-nanomolar activities (EC(50) 0.20-0.35nM). Compound 6a was more potent than progesterone (P4) in the in vivo decidualization assay in an ovariectomized female rat model by subcutaneous administration with an ED(50) of 1.5mg/kg (vs 5.62mg/kg for P4).
|
Binding affinity was determined against hPR-A (human progesterone receptor) using progesterone radioligand in competitive binding assay
|
None
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-Alkyl 1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal progesterone receptor modulators.
Year : 1998
Volume : 8
Issue : 23
First Page : 3365
Last Page : 3370
Authors : Zhi L, Tegley CM, Edwards JP, West SJ, Marschke KB, Gottardis MM, Mais DE, Jones TK.
Abstract : A series of nonsteroidal human progesterone receptor (hPR) agonists, 5-alkyl 1,2-dihydrochromeno[3,4-f]quinolines, was synthesized and evaluated in cotransfection and competitive receptor binding assays. The 5-alkyl substitution was shown to be responsible for the agonist activity and substitution at C9 dramatically enhanced the potency. A number of analogues in this series showed activities similar to or better than progesterone in the cotransfection and binding assays and analogue 15 exhibited similar in vivo activity as medroxyprogesterone acetate (MPA) in murine uterine wet weight/mammary gland morphology assays.
|
Binding affinity against human progesterone receptor
|
None
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 22
First Page : 4354
Last Page : 4359
Authors : Tegley CM, Zhi L, Marschke KB, Gottardis MM, Yang Q, Jones TK.
Abstract : A novel series of nonsteroidal progestins, 5-benzylidene-1, 2-dihydrochromeno[3,4-f]quinolines (2), was discovered, and a preliminary structure-activity relationship study around the 5-benzylidene ring generated several potent human progesterone receptor agonists (compounds 8, 16). These new progestins showed biological activities (EC50 = 5.7 and 7.6 nM) similar to progesterone (EC50 = 2.9 nM) in the cotransfection assay with high efficacy (132% and 166%) and binding affinity (Ki = 0.66 and 0.83 nM) similar to medroxyprogesterone acetate (MPA) (Ki = 0.34 nM). A representative analogue, 8, demonstrated similar oral potency to MPA in the uterine wet weight/mammary gland morphology assay in ovariectomized rats.
|
Binding affinity to human progesterone receptor
|
None
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives as progesterone receptor modulators.
Year : 2003
Volume : 13
Issue : 12
First Page : 2071
Last Page : 2074
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives were synthesized and tested in biological assays to evaluate scope and limitations of the nonsteroidal SPRM pharmacophore (3). A number of orally available highly potent nonsteroidal modulators were identified by modification of the substituents at 5-methylidene position.
|
Binding affinity against baculovirus expressed human Progesterone receptor
|
Homo sapiens
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2,3,4-tetrahydrochromeno[3,4-f]quinolin-3-ones as a novel class of nonsteroidal progesterone receptor agonists: effect of A-ring modification.
Year : 1999
Volume : 42
Issue : 8
First Page : 1466
Last Page : 1472
Authors : Zhi L, Tegley CM, Marschke KB, Mais DE, Jones TK.
Abstract : Optimization of the 1,2-dihydroquinoline A-ring of a nonsteroidal human progesterone receptor (hPR) agonist pharmacophore (1) was performed by using the cotransfection and receptor binding assays as guides. The 3-keto group was discovered to regain the potent agonist activity which was lost upon removal of the 3,4-olefin, and it led to a novel hPR agonist series, 5-aryl-1,2,3,4-tetrahydrochromeno[3, 4-f]quinolin-3-ones. The new progestins demonstrated potent hPR agonist activity in the cotransfection assay and high binding affinity similar to progesterone. T47D human breast cancer cell line was employed for further characterization of the new progestins and a number of reference analogues. It was found that the new 3-keto analogues showed full agonist activity in the T47D assay, while the reference compounds from other related nonsteroidal hPR agonist series exhibited only partial agonist activity.
|
The binding affinity on Human progesterone receptor (hPR-A) using progesterone as radioligand.
|
None
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 3
First Page : 291
Last Page : 302
Authors : Zhi L, Tegley CM, Kallel EA, Marschke KB, Mais DE, Gottardis MM, Jones TK.
Abstract : The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.
|
The binding affinity measured using baculovirus-expressed hPR-A in sf21 cells.
|
Homo sapiens
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-Aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines as potent, orally active, nonsteroidal progesterone receptor agonists: the effect of D-ring substituents.
Year : 1998
Volume : 41
Issue : 3
First Page : 303
Last Page : 310
Authors : Edwards JP, West SJ, Marschke KB, Mais DE, Gottardis MM, Jones TK.
Abstract : Several 5-(4-chlorophenyl)-1,2-dihydro-5H-chromeno[3,4-f]quinolines were prepared to determine the effects of substitution at C(8) and C(9) on the progestational activity of this pharmacophore. In combination with a halogen (F or Cl) at C(9), replacement of the C(5) aryl group with variously substituted aryl groups resulted in optimization of the progestational activity, affording compounds with in vitro activity greater than that of progesterone as measured by a cotransfection assay using human progesterone receptor subtype-B (hPR-B). Binding affinities (Ki) to hPR-A were subnanomolar in many cases. These in vitro effects were verified in vivo using a rodent model. Compound 10 (LG120794, 9-chloro-5-(4-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno++ +[3,4-f] quinoline) was more potent than medroxyprogesterone acetate at counterpoising the effects of estradiol benzoate in the uterine wet weight assay using immature rats.
|
Binding affinity against human progesterone receptor (hPR) in a competitive binding assay
|
None
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nonsteroidal progesterone receptor antagonists based on 6-thiophenehydroquinolines.
Year : 2000
Volume : 10
Issue : 5
First Page : 415
Last Page : 418
Authors : Zhi L, Tegley CM, Pio B, West SJ, Marschke KB, Mais DE, Jones TK.
Abstract : Synthesis and biological evaluation of 6-thiophene 1,2-dihydro or 1,2,3,4-tetrahydroquinoline derivatives resulted in a number of potent nonsteroidal antiprogestins.
|
Inhibition of [3H]R5020 binding to rabbit uterine progesterone receptor
|
Oryctolagus cuniculus
|
10.4
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of potential radioligands for the progesterone receptor.
Year : 1985
Volume : 28
Issue : 11
First Page : 1695
Last Page : 1699
Authors : Hoyte RM, Rosner W, Johnson IS, Zielinski J, Hochberg RB.
Abstract : Several steroidal analogues were synthesized as potential gamma-emitting radioligands for the progesterone receptor. Each of these compounds was tested as an inhibitor of the specific binding of [3H]-17 alpha,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione (R5020) to the progesterone receptor in rabbit uterine cytosol. R5020 is a well-known progestin with high affinity for the receptor. Of the compounds synthesized, aromatic N-substituted C-17 steroidal carboxamides inhibited the binding only poorly. Three compounds, 16 alpha-iodo-4-estren-17 beta-ol-3-one, 17 alpha-[2(E)-iodovinyl]-4-estren-17 beta-ol-3-one, and 17 alpha-[2(Z)-iodovinyl]-4-estren-17 beta-ol-3-one were excellent competitors, each having a Ki less than or equal to that of the natural progestin, progesterone. Since similar iodinated analogues of estrogens have been shown to be extremely stable both in vivo and in vitro, these compounds are potentially useful ligands for the progesterone receptor.
|
Displacement of [3H]progesterone at progesterone receptor of T47D cells
|
Homo sapiens
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel pyrrole-containing progesterone receptor modulators.
Year : 2004
Volume : 14
Issue : 9
First Page : 2185
Last Page : 2189
Authors : Collins MA, Hudak V, Bender R, Fensome A, Zhang P, Miller L, Winneker RC, Zhang Z, Zhu Y, Cohen J, Unwalla RJ, Wrobel J.
Abstract : A series of 1,4-dihydro-2H-[d][3,1]-benzoxazin-2-one and 1,3-dihydro-[3H]-indol-2-one containing 6- or 5-, respectively, appended substituted pyrrole moieties were synthesized and evaluated for their ability to modulate the activity of the progesterone receptor (PR). Key structural changes to the pyrrole moieties of these molecules were shown to have a predictive influence as to whether the compounds behaved as PR agonists or antagonists. Compounds with the 5(')-cyano-2(')-pyrrole moiety (e.g., 32, 33, and 38) were shown to be potent PR agonists (EC(50)'s of 1.1, 1.8, and 2.8 nM, respectively). Compounds with the 5(')-nitro-2(')-pyrrole moiety (e.g., 34 and 36) were shown to be PR antagonists (IC(50)'s of 180 and 36 nM, respectively).
|
Binding affinity towards human progesterone receptor A isoform using progesterone as radioligand
|
None
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : 5-benzylidene-1,2-dihydrochromeno[3,4-f]quinolines as selective progesterone receptor modulators.
Year : 2003
Volume : 46
Issue : 19
First Page : 4104
Last Page : 4112
Authors : Zhi L, Tegley CM, Pio B, Edwards JP, Motamedi M, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT.
Abstract : A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.
|
Binding affinity determined for human Progesterone receptor A isoform
|
None
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists based on cyclocymopol monomethyl ether.
Year : 1996
Volume : 39
Issue : 9
First Page : 1778
Last Page : 1789
Authors : Hamann LG, Farmer LJ, Johnson MG, Bender SL, Mais DE, Wang MW, Crombie D, Goldman ME, Jones TK.
Abstract : A novel class of nonsteroidal progesterone receptor antagonists has been synthesized and was shown to exhibit moderate binding affinity for hPR-A, the ability to inhibit the transcriptional activity of human progesterone receptor (hPR) in cell-based assays, and anti-progestational activity in a murine model. Cyclocymopol monomethyl ether, a component of the marine alga Cymopolia barbata was weakly active in random screening against PR. Investigations into the SAR surrounding the core of this natural product lead structure resulted in improved in vitro activity. In contrast to the cross-reactivity profiles observed with known steroidal antiprogestins, compounds of the general structural class described display a high degree of selectivity for the progesterone receptor and no functional activity on the glucocorticoid receptor.
|
Binding affinity for human progesterone receptor isoform A expressed in CV-1 cells
|
Homo sapiens
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : Preparation, resolution, and biological evaluation of 5-aryl-1, 2-dihydro-5H-chromeno[3,4-f]quinolines: potent, orally active, nonsteroidal progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 15
First Page : 2779
Last Page : 2785
Authors : Edwards JP, Zhi L, Pooley CL, Tegley CM, West SJ, Wang MW, Gottardis MM, Pathirana C, Schrader WT, Jones TK.
Abstract : Two potent nonsteroidal progestins from the 5-aryl-1, 2-dihydro-5H-chromeno[3,4-f]quinoline class (LG120746 and LG120747) were selected for scale-up, resolution, and biological evaluation of the purified enantiomers. For each quinoline, the levorotatory enantiomer was determined to be the more potent agonist of the human progesterone receptor isoform B (hPR-B) (EC50 < 3 nM), but the dextrorotatory enantiomers retained significant PR modulatory activity (EC50 < 200 nM). In two in vivo rodent models of progestational activity, a pregnancy maintenance assay and a uterine wet weight assay, the two eutomers displayed potent progesterone-like effects. In a third model for progestational activity, the mammary end bud assay, these compounds were significantly less active. These studies demonstrate that certain members of this class of selective progesterone receptor modulators display encouraging and potentially useful tissue-selective progestational effects.
|
Effective concentration for half-maximal activation of human progesterone receptor expressed in CV-1 cells
|
Homo sapiens
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Preparation, resolution, and biological evaluation of 5-aryl-1, 2-dihydro-5H-chromeno[3,4-f]quinolines: potent, orally active, nonsteroidal progesterone receptor agonists.
Year : 1998
Volume : 41
Issue : 15
First Page : 2779
Last Page : 2785
Authors : Edwards JP, Zhi L, Pooley CL, Tegley CM, West SJ, Wang MW, Gottardis MM, Pathirana C, Schrader WT, Jones TK.
Abstract : Two potent nonsteroidal progestins from the 5-aryl-1, 2-dihydro-5H-chromeno[3,4-f]quinoline class (LG120746 and LG120747) were selected for scale-up, resolution, and biological evaluation of the purified enantiomers. For each quinoline, the levorotatory enantiomer was determined to be the more potent agonist of the human progesterone receptor isoform B (hPR-B) (EC50 < 3 nM), but the dextrorotatory enantiomers retained significant PR modulatory activity (EC50 < 200 nM). In two in vivo rodent models of progestational activity, a pregnancy maintenance assay and a uterine wet weight assay, the two eutomers displayed potent progesterone-like effects. In a third model for progestational activity, the mammary end bud assay, these compounds were significantly less active. These studies demonstrate that certain members of this class of selective progesterone receptor modulators display encouraging and potentially useful tissue-selective progestational effects.
|
Effective concentration on alkaline phosphatase activity in human T47D breast carcinoma cell line.
|
Homo sapiens
|
0.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel 6-aryl-1,4-dihydrobenzo[d]oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists.
Year : 2003
Volume : 13
Issue : 7
First Page : 1313
Last Page : 1316
Authors : Zhang P, Terefenko EA, Fensome A, Wrobel J, Winneker R, Zhang Z.
Abstract : The functional activity of 6-aryl benzoxazinone-based progesterone (PR) antagonists changed to PR agonism when the 2-carbonyl group was replaced by a 2-thiocarbonyl moiety. Based on this finding novel 6-aryl benzoxazine-2-thiones were synthesized and evaluated as PR agonists in various in vitro and in vivo assays. Several analogues had sub-nanomolar in vitro potency and showed excellent oral activities in rats. Compounds 15 and 29 had similar potencies to medroxyprogesterone acetate (MPA) in the in vitro T47D alkaline phosphatase assay and in vivo rat decidualization model. In contrast to MPA, 29 was highly selective (>500-fold) for PR over glucocorticoid and androgen receptors.
|
Affinity for sigma receptor type 1 of guinea pig using [3H]ifenprodil or (+)-[3H]pentazocine radioligand
|
Cavia porcellus
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of high-affinity ligands of sigma1 receptor, ERG2, and emopamil binding protein by pharmacophore modeling and virtual screening.
Year : 2005
Volume : 48
Issue : 15
First Page : 4754
Last Page : 4764
Authors : Laggner C, Schieferer C, Fiechtner B, Poles G, Hoffmann RD, Glossmann H, Langer T, Moebius FF.
Abstract : ERG2, emopamil binding protein (EBP), and sigma-1 receptor (sigma(1)) are enzymes of sterol metabolism and an enzyme-related protein, respectively, that share high affinity for various structurally diverse compounds. To discover novel high-affinity ligands, pharmacophore models were built with Catalyst based upon a series of 23 structurally diverse chemicals exhibiting K(i) values from 10 pM to 100 microM for all three proteins. In virtual screening experiments, we retrieved drugs that were previously reported to bind to one or several of these proteins and also tested 11 new hits experimentally, of which three, among them raloxifene, had affinities for sigma(1) or EBP of <60 nM. When used to search a database of 3525 biochemicals of intermediary metabolism, a slightly modified ERG2 pharmacophore model successfully retrieved 10 substrate candidates among the top 28 hits. Our results indicate that inhibitor-based pharmacophore models for sigma(1), ERG2, and EBP can be used to screen drug and metabolite databases for chemically diverse compounds and putative endogenous ligands.
|
Displacement of [3H]progesterone from Progesterone receptor
|
Homo sapiens
|
3.467
nM
|
|
Journal : J. Med. Chem.
Title : Docking and three-dimensional quantitative structure-activity relationship (3D QSAR) analyses of nonsteroidal progesterone receptor ligands.
Year : 2006
Volume : 49
Issue : 14
First Page : 4261
Last Page : 4268
Authors : Söderholm AA, Lehtovuori PT, Nyrönen TH.
Abstract : We report a docking and comparative molecular similarity indices analysis (CoMSIA) study of progesterone receptor (PR) ligands with an emphasis on nonsteroids including tanaproget. The ligand alignment generation, a critical part of model building, comprised two stages. First, thorough conformational sampling of docking poses within the PR binding pocket was made with the program GOLD. Second, a strategy to select representative poses for CoMSIA was developed utilizing the FlexX scoring function. After manual replacement of five poses where this approach had problems, a significant correlation (r(2) = 0.878) between the experimental affinities and electrostatic, hydrophobic, and hydrogen bond donor properties of the aligned ligands was found. Extensive model validation was made using random-group cross-validations, external test set predictions (r(pred)(2) = 0.833), and consistency check between the CoMSIA model and the PR binding site structure. Robustness, predictive ability, and automated alignment generation make the model a potential tool for virtual screening.
|
Displacement of [3H]5alpha dihydrotestosterone from human sex hormone binding globulin
|
Homo sapiens
|
114.82
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.
|
Antiinflammatory activity in Swiss mouse assessed as inhibition of serotonin-induced ear edema at 50 mg/kg, sc in presence of progesterone administered 1 hr prior to compound treatment
|
Mus musculus
|
44.0
%
|
|
Journal : J. Nat. Prod.
Title : Anti-inflammatory activity of saikosaponins from Heteromorpha trifoliata.
Year : 1995
Volume : 58
Issue : 1
First Page : 140
Last Page : 144
Authors : Recio MC, Just MJ, Giner RM, Mañez S, Rios JL, Hostettmann K.
Abstract : By means of activity-directed chromatographic fractionation using the 12-O-tetradecanoylphorbol acetate (TPA)-induced edema test, two saikosaponins were isolated from the MeOH extract of Heteromorpha trifoliata leaves. They were identified as 16 beta, 23-dihydroxy-13,28-epoxyolean-11-en-3 beta-yl-[beta-D-glucopyranosyl (1-->2)]-[beta-D-glucopyranosyl (1-->3)]-beta-D-fucopyranoside [1] and 16 beta, 23,28-trihydroxy-11 alpha-methoxyolean-12-en-3 beta-yl-[beta-D-glucopyranosyl (1-->2)]-[beta-D-glucopyranosyl (1-->3) [beta-D-fucopyranoside [2]. Compound 1 showed activity in the TPA and ethylphenylpropiolate (EPP) mouse ear edema and the serotonin paw edema tests, whereas compound 2 was active only in the mouse ear edema model. Both substances had only a slight effect against a carrageenan paw edema model. The anti-inflammatory action of compound 1 was notably decreased by the mRNA and protein synthesis inhibitors actinomycin D and cycloheximide.
|
Agonist activity at human progesterone receptor
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : A tissue-selective nonsteroidal progesterone receptor modulator: 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4-f]quinoline.
Year : 2008
Volume : 51
Issue : 13
First Page : 3696
Last Page : 3699
Authors : Pedram B, van Oeveren A, Mais DE, Marschke KB, Verbost PM, Groen MB, Zhi L.
Abstract : The progesterone receptor plays an important role in the female reproductive system. Here we describe the discovery of a new selective progesterone receptor modulator (SPRM). In rats, the lead compound, 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4- f]quinoline ( 5c), inhibited ovulation and showed full efficacy in uterine and vaginal tissue but was a mixed partial agonist/antagonist in breast tissue. The compound also suppressed ovulation in monkeys, but in contrast to currently approved steroidal PR agonists, it did not suppress estradiol levels.
|
Agonist activity at human progesterone receptor in human T47D cells assessed as alkaline phosphatase activity
|
Homo sapiens
|
2.2
nM
|
|
Journal : J. Med. Chem.
Title : A tissue-selective nonsteroidal progesterone receptor modulator: 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4-f]quinoline.
Year : 2008
Volume : 51
Issue : 13
First Page : 3696
Last Page : 3699
Authors : Pedram B, van Oeveren A, Mais DE, Marschke KB, Verbost PM, Groen MB, Zhi L.
Abstract : The progesterone receptor plays an important role in the female reproductive system. Here we describe the discovery of a new selective progesterone receptor modulator (SPRM). In rats, the lead compound, 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4- f]quinoline ( 5c), inhibited ovulation and showed full efficacy in uterine and vaginal tissue but was a mixed partial agonist/antagonist in breast tissue. The compound also suppressed ovulation in monkeys, but in contrast to currently approved steroidal PR agonists, it did not suppress estradiol levels.
|
Binding affinity at human progesterone receptor
|
Homo sapiens
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : A tissue-selective nonsteroidal progesterone receptor modulator: 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4-f]quinoline.
Year : 2008
Volume : 51
Issue : 13
First Page : 3696
Last Page : 3699
Authors : Pedram B, van Oeveren A, Mais DE, Marschke KB, Verbost PM, Groen MB, Zhi L.
Abstract : The progesterone receptor plays an important role in the female reproductive system. Here we describe the discovery of a new selective progesterone receptor modulator (SPRM). In rats, the lead compound, 7,9-difluoro-5-(3-methylcyclohex-2-enyl)-2,2,4-trimethyl-1,2-dihydrochromeno[3,4- f]quinoline ( 5c), inhibited ovulation and showed full efficacy in uterine and vaginal tissue but was a mixed partial agonist/antagonist in breast tissue. The compound also suppressed ovulation in monkeys, but in contrast to currently approved steroidal PR agonists, it did not suppress estradiol levels.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
55.7
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Activity at progesterone receptor assessed as alkaline phosphatase activity in human T47D cells
|
Homo sapiens
|
0.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1,5-Dihydro-benzo[e][1,4]oxazepin-2(1H)-ones containing a 7-(5'-cyanopyrrol-2-yl) group as nonsteroidal progesterone receptor modulators.
Year : 2008
Volume : 18
Issue : 18
First Page : 5015
Last Page : 5017
Authors : Kern JC, Terefenko EA, Fensome A, Unwalla R, Wrobel J, Cohen J, Zhu Y, Berrodin TJ, Yudt MR, Winneker RC, Zhang Z, Zhang P.
Abstract : A series of novel 7-(5'-cyanopyrrol-2-yl) substituted benzo[1,4]oxazepin-2-ones were prepared and tested for their progesterone receptor (PR) agonist or antagonist activity in the alkaline phosphatase assay using the human T47D breast carcinoma cell line. Both PR agonists and antagonists were achieved with an appropriate choice of 5-substitution. Several analogs were potent PR agonists (e.g., 12 and 13) or PR antagonists (e.g., 18) with good selectivity over other steroid receptors.
|
Displacement of 1-anilinonaphthalene-8-sulphonic acid from rat recombinant L-FABP high binding affinity site expressed in Escherichia coli BL21 by competitive fluorescence displacement assay
|
Rattus norvegicus
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Characterization of the drug binding specificity of rat liver fatty acid binding protein.
Year : 2008
Volume : 51
Issue : 13
First Page : 3755
Last Page : 3764
Authors : Chuang S, Velkov T, Horne J, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in the cytosolic solubilization of fatty acids during fat absorption. In the current studies, the interaction of L-FABP with a range of lipophilic drugs has been evaluated to explore the potential for L-FABP to provide an analogous function during the absorption of lipophilic drugs. Binding affinity for L-FABP was assessed by displacement of a fluorescent marker, 1-anilinonaphthalene-8-sulfonic acid (ANS), and the binding site location was determined via nuclear magnetic resonance chemical shift perturbation studies. It was found that the majority of drugs bound to L-FABP at two sites, with the internal site generally having a higher affinity for the compounds tested. Furthermore, in contrast to the interaction of L-FABP with fatty acids, it was demonstrated that a terminal carboxylate is not required for specific binding of lipophilic drugs at the internal site of L-FABP.
|
Inhibition of glutamate-induced excitotoxicity in rat E18 cells assessed as reduction in cell death at 20 uM pretreated for 24 hrs before glutamate challenge measured after 24 hrs by MTT assay
|
Rattus norvegicus
|
42.0
%
|
|
Journal : J. Med. Chem.
Title : Development and screening of water-soluble analogues of progesterone and allopregnanolone in models of brain injury.
Year : 2009
Volume : 52
Issue : 19
First Page : 6012
Last Page : 6023
Authors : MacNevin CJ, Atif F, Sayeed I, Stein DG, Liotta DC.
Abstract : Preclinical and clinical research findings have revealed that the hormone progesterone, when acutely administered, can dramatically reduce cerebral edema, inflammation, tissue necrosis, and programmed cell death following traumatic brain injury (TBI). The poor aqueous solubility of progesterone, however, limits its potential use as a therapeutic. Several chemically novel analogues of progesterone and its natural metabolite allopregnanolone have been synthesized and screened using both in vitro and whole animal models of TBI. The new derivatives demonstrated greatly improved solubility and select compounds have shown equivalent effectiveness to progesterone in reducing cerebral edema after TBI.
|
Inhibition of glutamate-induced excitotoxicity in rat E18 cells assessed as reduction in cell death at 5 uM pretreated for 24 hrs before glutamate challenge measured after 24 hrs by MTT assay
|
Rattus norvegicus
|
4.0
%
|
|
Journal : J. Med. Chem.
Title : Development and screening of water-soluble analogues of progesterone and allopregnanolone in models of brain injury.
Year : 2009
Volume : 52
Issue : 19
First Page : 6012
Last Page : 6023
Authors : MacNevin CJ, Atif F, Sayeed I, Stein DG, Liotta DC.
Abstract : Preclinical and clinical research findings have revealed that the hormone progesterone, when acutely administered, can dramatically reduce cerebral edema, inflammation, tissue necrosis, and programmed cell death following traumatic brain injury (TBI). The poor aqueous solubility of progesterone, however, limits its potential use as a therapeutic. Several chemically novel analogues of progesterone and its natural metabolite allopregnanolone have been synthesized and screened using both in vitro and whole animal models of TBI. The new derivatives demonstrated greatly improved solubility and select compounds have shown equivalent effectiveness to progesterone in reducing cerebral edema after TBI.
|
Inhibition of human 17beta-HSD7 expressed in HEK293 cells assessed as inhibition of reduction of [14C]estrone into [14C]estradiol at 0.3 uM after 7 hrs
|
Homo sapiens
|
7.3
%
|
|
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.
|
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
|
19.1
%
|
|
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.
|
Activation of progesterone receptor in human T47D cells after 20 hrs by PRE-tagged luciferase reporter gene assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : J. Nat. Prod.
Title : The lecanindoles, nonsteroidal progestins from the terrestrial fungus Verticillium lecanii 6144.
Year : 2009
Volume : 72
Issue : 11
First Page : 1944
Last Page : 1948
Authors : Roll DM, Barbieri LR, Bigelis R, McDonald LA, Arias DA, Chang LP, Singh MP, Luckman SW, Berrodin TJ, Yudt MR.
Abstract : Four new indolosesquiterpenes, lecanindoles A-D (1-4), were isolated from fermentations of the terrestrial fungus Verticillium lecanii 6144. The structures of compounds 1-4 were elucidated from analysis of spectroscopic data. Compound 2 was reduced to give 4 and its isomer 5. Compound 4 was found to be a potent and selective progesterone receptor agonist with an EC50 of 1.1 +/- 0.4 nM in a cell-based luciferase reporter assay.
|
Displacement of [3H]DHT from human androgen receptor after 16 hrs by scintillation counting
|
Homo sapiens
|
35.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Aromatic beta-amino-ketone derivatives as novel selective non-steroidal progesterone receptor antagonists.
Year : 2010
Volume : 18
Issue : 12
First Page : 4255
Last Page : 4268
Authors : Du Y, Li Q, Xiong B, Hui X, Wang X, Feng Y, Meng T, Hu D, Zhang D, Wang M, Shen J.
Abstract : A novel class of non-steroidal progesterone receptor antagonists with aromatic beta-amino-ketone scaffold have been synthesized and characterized with high binding affinity and great selectivity for the cognate receptors. Among them, compound 22 was shown to be the most potent progesterone receptor antagonist in cotransfection assay and a murine model of ligand-induced decidualization.
|
Displacement of [3H]progesterone from human progesterone receptor B after 16 hrs by scintillation counting
|
Homo sapiens
|
5.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Aromatic beta-amino-ketone derivatives as novel selective non-steroidal progesterone receptor antagonists.
Year : 2010
Volume : 18
Issue : 12
First Page : 4255
Last Page : 4268
Authors : Du Y, Li Q, Xiong B, Hui X, Wang X, Feng Y, Meng T, Hu D, Zhang D, Wang M, Shen J.
Abstract : A novel class of non-steroidal progesterone receptor antagonists with aromatic beta-amino-ketone scaffold have been synthesized and characterized with high binding affinity and great selectivity for the cognate receptors. Among them, compound 22 was shown to be the most potent progesterone receptor antagonist in cotransfection assay and a murine model of ligand-induced decidualization.
|
Agonist activity at human progesterone receptor B expressed in african green monkey CV1 cells co-transfected with MMTV-Luc after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
15.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Aromatic beta-amino-ketone derivatives as novel selective non-steroidal progesterone receptor antagonists.
Year : 2010
Volume : 18
Issue : 12
First Page : 4255
Last Page : 4268
Authors : Du Y, Li Q, Xiong B, Hui X, Wang X, Feng Y, Meng T, Hu D, Zhang D, Wang M, Shen J.
Abstract : A novel class of non-steroidal progesterone receptor antagonists with aromatic beta-amino-ketone scaffold have been synthesized and characterized with high binding affinity and great selectivity for the cognate receptors. Among them, compound 22 was shown to be the most potent progesterone receptor antagonist in cotransfection assay and a murine model of ligand-induced decidualization.
|
Binding affinity to progesterone receptor
|
None
|
0.2
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140.
Year : 2011
Volume : 2
Issue : 2
First Page : 124
Last Page : 129
Authors : Miller CP, Shomali M, Lyttle CR, O'Dea LS, Herendeen H, Gallacher K, Paquin D, Compton DR, Sahoo B, Kerrigan SA, Burge MS, Nickels M, Green JL, Katzenellenbogen JA, Tchesnokov A, Hattersley G.
Abstract : This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.
|
Displacement of [3H]progesterone from rabbit PR by liquid scintillation counting
|
Oryctolagus cuniculus
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of tricyclic tetrahydroquinolines as a new series of nonsteroidal selective androgen receptor modulators (SARMs).
Year : 2011
Volume : 21
Issue : 6
First Page : 1744
Last Page : 1747
Authors : Nagata N, Miyakawa M, Amano S, Furuya K, Yamamoto N, Inoguchi K.
Abstract : Some tricyclic tetrahydroquinolines (THQs) were found to have the potential of a new series of nonsteroidal selective androgen receptor modulators (SARMs). Compound 5b was first designed and synthesized under our hypothesis based on a four-point pharmacophoric requirement of the 3-carbonyl, 18-methyl, 17-hydroxyl, and 13-quaternary carbon groups of dihydrotestosterone (DHT). It was revealed that this compound exhibits not only a strong androgen receptor (AR) agonistic activity (EC(50)=9.2 nM) but also the highest selectivity in binding affinity to AR among the steroid hormone receptors. Furthermore, this compound showed a weak virilizing effect with retention of the desired anabolic effect as compared with DHT in vivo.
|
Displacement of (+)-[3H]pentazocine from guinea pig brain sigma 1 receptor after 180 mins by scintillation counting
|
Cavia porcellus
|
660.0
nM
|
|
Journal : J. Med. Chem.
Title : Combination of two pharmacophoric systems: synthesis and pharmacological evaluation of spirocyclic pyranopyrazoles with high σ₁ receptor affinity.
Year : 2011
Volume : 54
Issue : 19
First Page : 6704
Last Page : 6713
Authors : Schläger T, Schepmann D, Lehmkuhl K, Holenz J, Vela JM, Buschmann H, Wünsch B.
Abstract : The novel class of spirocyclic σ(1) ligands 3 (6',7'-dihydro-1'H-spiro[piperidine-4,4'-pyrano[4,3-c]pyrazoles]) was designed by the combination of the potent σ(1) ligands 1 and 2 in one molecule. Thorough structure affinity relationships were derived by the variation of the substituents in position 1', 1, and 6'. Whereas the small electron rich methylpyrazole heterocycle was less tolerated by the σ(1) receptor protein, the introduction of a phenyl substituent instead of the methyl group led to ligands with a high σ(1) affinity. It is postulated that the additional phenyl substituent occupies a previously unrecognized hydrophobic region of the σ(1) receptor resulting in additional lipophilic interactions. The spirocyclic pyranopyrazoles are very selective against the σ(2) subtype, the PCP binding site of the NMDA receptor, and further targets. Despite high σ(1) affinity, the cyclohexylmethyl derivative 17i (K(i) (σ(1)) = 0.55 nM) and the isopentenyl derivative 17p (K(i) (σ(1)) = 1.6 nM) showed only low antiallodynic activity in the capsaicin assay.
|
DRUGMATRIX: Progesterone radioligand binding (ligand: [3H] R-5020)
|
Bos taurus
|
28.0
nM
|
|
DRUGMATRIX: Progesterone radioligand binding (ligand: [3H] R-5020)
|
Bos taurus
|
3.622
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
|
DRUGMATRIX: Androgen (Testosterone) AR radioligand binding (ligand: [3H] Mibolerone)
|
Escherichia coli
|
214.0
nM
|
|
DRUGMATRIX: Androgen (Testosterone) AR radioligand binding (ligand: [3H] Mibolerone)
|
Escherichia coli
|
143.0
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
|
DRUGMATRIX: Glucocorticoid radioligand binding (ligand: [3H] Dexamethasone)
|
None
|
330.0
nM
|
|
DRUGMATRIX: Glucocorticoid radioligand binding (ligand: [3H] Dexamethasone)
|
None
|
150.0
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
|
Displacement of [3H]progesterone from progesterone receptor in JW rabbit uterus after 2 hrs by liquid scintillation counting
|
Oryctolagus cuniculus
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tetrahydroquinolines as a novel series of nonsteroidal selective androgen receptor modulators: structural requirements for better physicochemical and biological properties.
Year : 2011
Volume : 21
Issue : 21
First Page : 6310
Last Page : 6313
Authors : Nagata N, Miyakawa M, Amano S, Furuya K, Yamamoto N, Nejishima H, Inoguchi K.
Abstract : A rationally designed tetrahydroquinoline (1) for nonsteroidal selective androgen receptor modulators was modified for the exploration of promising compounds by Grieco three-component condensation using various dienophiles. Based on the in vitro effects and physicochemical properties of the synthesized compounds, compound 4c was selected for further study. Compound 4c increased the femoral bone mineral density as much as DHT, but it reduced the uterus effect compared with DHT in ovariectomized rats. Thus, compound 4c has desirable osteoanabolic effects with weak undesirable effects on the uterus in a female osteoporosis model.
|
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
|
63.9
%
|
|
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 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
|
33.4
%
|
|
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
|
-362.6
%
|
|
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.
|
Displacement of [3H](+)-Pentazocine from sigma 1 receptor in guinea pig brain membranes after 120 mins by scintillation counting analysis
|
Cavia porcellus
|
661.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones.
Year : 2013
Volume : 21
Issue : 7
First Page : 1844
Last Page : 1856
Authors : Meyer C, Neue B, Schepmann D, Yanagisawa S, Yamaguchi J, Würthwein EU, Itami K, Wünsch B.
Abstract : The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective α-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2'-bipyridyl/Ag2CO3, whereas the β-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/P[OCH(CF3)2]3/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both α-positions providing 4'-mono-, 6'-mono- and 4',6'-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1'-position of 13, 3'-position of 14, 4'-position of 18) showed increased σ1 affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2'-position in 20a) also increased the σ1 affinity but to a lower extent. A considerable reduction of σ1 affinity was observed after introducing an aryl moiety in 6'-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the σ1 receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products.
|
Cytotoxicity against human HeLa cells after 48 hrs by MTT assay
|
Homo sapiens
|
50.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and cytotoxic activity of some novel steroidal C-17 pyrazolinyl derivatives.
Year : 2013
Volume : 69
First Page : 182
Last Page : 190
Authors : Fan NJ, Tang JJ, Li H, Li XJ, Luo B, Gao JM.
Abstract : Fourteen novel steroidal C-17 pyrazolinyl derivatives 9a-g and 10a-g were synthesized from commercially available progesterone and tested for their cytotoxic activity against brine shrimp (Artemia salina) and three human cancer cell lines (NCI-H460, HeLa, and HepG2). Some of these synthetic compounds exhibited significant cytotoxic activity, and treatment of HeLa cells with compound 10b resulted in the cell population arrest in the S phase. A structure-activity relationship was discussed.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
52.43
%
|
|
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
|
92.0
%
|
|
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.
|
Displacement of [3H]ditolylguanidine from sigma-2 opioid receptor in rat liver membranes by liquid scintillation spectrometric analysis
|
Rattus norvegicus
|
441.0
nM
|
|
Journal : J. Med. Chem.
Title : The σ2 receptor: a novel protein for the imaging and treatment of cancer.
Year : 2013
Volume : 56
Issue : 18
First Page : 7137
Last Page : 7160
Authors : Mach RH, Zeng C, Hawkins WG.
Abstract : The σ2 receptor is an important target for the development of molecular probes in oncology because of its 10-fold higher density in proliferating tumor cells compared with that in quiescent tumor cells and because of the observation that σ2 receptor agonists are able to kill tumor cells via apoptotic and nonapoptotic mechanisms. Although recent evidence indicates that the σ2 receptor binding site is localized within the progesterone receptor membrane component 1 (PGRMC1), most information regarding this protein has been obtained using either radiolabeled or fluorescent receptor-based probes and from biochemical analysis of the effect of σ2 selective ligands on cells grown in culture. This article reviews the development of σ2 receptor ligands and presents an overview of how they have been used in vitro and in vivo to increase our understanding of the role of the σ2 receptor in cancer and proliferation.
|
Displacement of [3H]pentazocine from sigma-1 opioid receptor in rat liver membranes after 1 hr by liquid scintillation spectrometric analysis
|
Rattus norvegicus
|
239.0
nM
|
|
Journal : J. Med. Chem.
Title : The σ2 receptor: a novel protein for the imaging and treatment of cancer.
Year : 2013
Volume : 56
Issue : 18
First Page : 7137
Last Page : 7160
Authors : Mach RH, Zeng C, Hawkins WG.
Abstract : The σ2 receptor is an important target for the development of molecular probes in oncology because of its 10-fold higher density in proliferating tumor cells compared with that in quiescent tumor cells and because of the observation that σ2 receptor agonists are able to kill tumor cells via apoptotic and nonapoptotic mechanisms. Although recent evidence indicates that the σ2 receptor binding site is localized within the progesterone receptor membrane component 1 (PGRMC1), most information regarding this protein has been obtained using either radiolabeled or fluorescent receptor-based probes and from biochemical analysis of the effect of σ2 selective ligands on cells grown in culture. This article reviews the development of σ2 receptor ligands and presents an overview of how they have been used in vitro and in vivo to increase our understanding of the role of the σ2 receptor in cancer and proliferation.
|
Agonist activity at human PRGR expressed in HEK293 cells by luciferase reporter gene assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt.
Year : 2014
Volume : 24
Issue : 22
First Page : 5265
Last Page : 5267
Authors : Gege C, Schlüter T, Hoffmann T.
Abstract : Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) is a key transcription factor for the development of Th17 cells. Inhibiting RORγt activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently N-(5-(arylcarbonyl)thiazol-2-yl)amides were described as RORγt antagonists with in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) via oral administration. So far no selective small molecule ligands have been revealed for RORβ. We show, that one compound of this class, namely N-[5-(2-chloro-benzoyl)-4-(3-chlorophenyl)-thiazol-2-yl]-2-(4-ethanesulfonyl-phenyl)-acetamide (4) is a potent dual inverse agonist towards RORγt and RORβ devoid of activity to 18 other human nuclear receptors and thus can serve as chemical probe to deepen our understanding about RORβ and its biology.
|
Induction of mitochondrial dysfunction in Sprague-Dawley rat liver mitochondria assessed as inhibition of mitochondrial respiration per mg mitochondrial protein measured for 20 mins by A65N-1 oxygen probe based fluorescence assay
|
Rattus norvegicus
|
100.0
nM
|
|
Journal : Hepatology
Title : Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump.
Year : 2014
Volume : 60
Issue : 3
First Page : 1015
Last Page : 1022
Authors : Aleo MD, Luo Y, Swiss R, Bonin PD, Potter DM, Will Y.
Abstract : Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs.These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI.
|
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
|
12.63
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
3.02
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
23.48
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
17.62
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
21.89
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
11.36
%
|
|
|
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
|
-1.48
%
|
|
|
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
|
3.27
%
|
|
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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Competitive displacement of [3H]R1881 from human AR-LBD expressed in LNCaP cells incubated for 24 hrs by scintillation counting method based radioligand competitive binding assay
|
Homo sapiens
|
13.7
nM
|
|
Journal : Eur J Med Chem
Title : Discovery and biological evaluation of novel androgen receptor antagonist for castration-resistant prostate cancer.
Year : 2019
Volume : 171
First Page : 265
Last Page : 281
Authors : Yu J, Zhang L, Yan G, Zhou P, Cao C, Zhou F, Li X, Chen Y.
Abstract : Prostate cancer (PC) is the second most common malignancy in men worldwide. Among current therapies, two antiandrogens, Abiraterone Acetate and Enzalutamide (Enza) have become the standard of care for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we designed and synthesized a new series of nonsteroidal compounds deriving from the hybridization of Abiraterone (Abi) and Enzalutamide, among which compound 4a featuring the diphenylamine scaffold was identified as a potent and cell selective androgen receptor (AR) antagonist. In cell proliferation assays, compound 4a exhibited better antiproliferative activities than Enzalutamide against AR-overexpressing VCaP cells and 22Rv1 cells bearing H874Y-mutated AR. In addition, 4a suppressed the activity of AR-F876L mutant that confers resistance to Enzalutamide and efficiently blocked R1881-induced PSA and FKBP5 gene expression. In competitive binding assay, compound 4a displayed higher binding affinity to AR than Enzalutamide. These results suggest compound 4a as a potential candidate to treat Enza-resistant CRPC.
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Agonist activity at PR (unknown origin) by Alpha Screen assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : MedChemComm
Title : Dissecting the allosteric FXR modulation: a chemical biology approach using guggulsterone as a chemical tool.
Year : 2019
Volume : 10
Issue : 8
First Page : 1412
Last Page : 1419
Authors : Passeri D, Carotti A, Pittol JMR, Ciaccioli G, Pellicciari R, van Mil SWC, Gioiello A.
Abstract : Guggulsterone is a promiscuous ligand for endocrine and metabolic lipid receptors traditionally used to treat a number of diseases including diabesity, hyperlipidemia, atherosclerosis, and osteoarthritis. Although relatively weak, its activity at the farnesoid X receptor (FXR) is particularly intriguing as guggulsterone acts as an antagonist with a peculiar ability of gene selective modulation. We report here a chemical biology study with the aim to further characterize the biological action of guggulsterone at the FXR and to obtain further insights into the functional role played by noncanonical FXR binding pockets S2 and S3. Our results suggest that the FXR accessory pockets might act as potential targets for small molecules able to modulate the metabolic activation of the receptor without affecting the anti-inflammatory activity thus revealing a new approach for disclosing selective FXR modulators that might bypass potential side-effects from chronic treatments.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.95
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
22.04
%
|
|
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
|
0.43
%
|
|
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
|
1.99
%
|
|
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
|
0.43
%
|
|
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
|
1.99
%
|
|
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.
|
Agonist activity at human PR
|
Homo sapiens
|
50.0
nM
|
|
Journal : J Med Chem
Title : Discovery of 3α,7α,11β-Trihydroxy-6α-ethyl-5β-cholan-24-oic Acid (TC-100), a Novel Bile Acid as Potent and Highly Selective FXR Agonist for Enterohepatic Disorders.
Year : 2016
Volume : 59
Issue : 19
First Page : 9201
Last Page : 9214
Authors : Pellicciari R,Passeri D,De Franco F,Mostarda S,Filipponi P,Colliva C,Gadaleta RM,Franco P,Carotti A,Macchiarulo A,Roda A,Moschetta A,Gioiello A
Abstract : As a continuation of previous efforts in mapping functional hot spots on the bile acid scaffold, we here demonstrate that the introduction of a hydroxy group at the C11β position affords high selectivity for FXR. In particular, the synthesis and FXR/TGR5 activity of novel bile acids bearing different hydroxylation patterns at the C ring are reported and discussed from a structure-activity standpoint. The results obtained led us to discover the first bile acid derivative endowed with high potency and selectivity at the FXR receptor, 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid (TC-100, 7) which also shows a remarkable physicochemical and pharmacological profile. Compound 7 combines the excellent physicochemical properties of hydrophilic bile acids such as ursodeoxycholic acid, with the distinct ability to specifically bind and regulate FXR activity in vivo, thus providing a bona fide novel therapeutic agent to treat enterohepatic disorders such as cholestasis, NASH, and inflammatory bowel disease.
|
Agonist activity at PR in human T47D cells using p-nitrophenyl phosphate as substrate assessed as induction of alkaline phosphatase activity incubated for 72 hrs followed by substrate addition measured after 24 hrs by alkaline phosphatase assay
|
Homo sapiens
|
0.18
nM
|
|
