|
Inhibition of Calmodulin activation of cyclic nucleotide phosphodiesterase
|
Homo sapiens
|
6.0
%
|
|
Journal : J. Med. Chem.
Title : Antiestrogens. 3. Estrogen receptor affinities and antiproliferative effects in MCF-7 cells of phenolic analogues of trioxifene, [3,4-dihydro-2-(4- methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]- phenyl]methanone.
Year : 1992
Volume : 35
Issue : 5
First Page : 931
Last Page : 938
Authors : Jones CD, Blaszczak LC, Goettel ME, Suarez T, Crowell TA, Mabry TE, Ruenitz PC, Srivatsan V.
Abstract : Benzothiophenes 3 and 4, derived from the acrylophenone antiestrogen trioxifene (2), are characterized by high estrogen receptor (ER) affinity and low residual estrogenicity compared to tamoxifen (1a). In order to characterize further the growth suppression mechanism for these structural types we have prepared structural variants of 2 bearing hydroxy groups positioned to maximize ER affinity. Thus, dihydronaphthalenes 5 and 6 and benzofluorenes 7 and 8 were prepared and studied in MCF-7 human breast cancer cells, in comparison with 3 and 4. All compounds were powerful suppressants of cell growth, with 50% inhibition ranging from 4.5 to 160 nM. Greatest potency was seen with diphenols 6 and 8. These compounds had intracellular ER affinities ranging from 0.2 to 4.1% of that of estradiol, suggestive of a potential for partial agonist effects. Simultaneous exposure of cells to 0.1 microM concentrations of estradiol and 3 or 4 did not affect the degree of growth inhibition seen with 0.1 microM 3 or 4 alone. Partial reversal of inhibition occurred when 0.1 microM 5-8 were each accompanied by 0.1 microM estradiol. Under these conditions complete reversal of growth inhibition has been found with 1a, 1b, and other triarylethylenes. Calmodulin, a putative target for triarylethylenes, and which is antagonized by 1a, was shown to interact weakly with 7 and 8 and not at all with 3-6. These results suggest that MCF-7 cell growth suppression by 3-8 may be due to interaction with unidentified receptors besides ER and extend earlier findings indicating that events occurring after interaction of these compounds with ER differ from those of triarylethylene antiestrogens.
|
Stimulation of alkaline phosphatase activity in Ishikawa human endometrial adenocarcinoma cells
|
Homo sapiens
|
0.04
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel thio-substituted chromanes as high-affinity partial agonists for the estrogen receptor.
Year : 2002
Volume : 12
Issue : 1
First Page : 17
Last Page : 19
Authors : Christiansen LB, Wenckens M, Bury PS, Gissel B, Hansen BS, Thorpe SM, Jacobsen P, Kanstrup A, Jørgensen AS, Naerum L, Wassermann K.
Abstract : Synthesis of (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-piperidinoethanethio)phenyl)chromane (13) and (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethanethio)phenyl)chromane (15) is presented. These compounds are representatives of a novel class of compounds with high in vitro binding affinity for the estrogen receptor (IC(50)=7-10 nM), and very low in vitro uterotrophic activity (max stim.=5-17% rel to moxestrol; EC(50)=0.5-1.8 nM).
|
Displacement of [3H]estradiol from Estrogen receptor in MCF-7 cells
|
Homo sapiens
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Antiestrogens. 3. Estrogen receptor affinities and antiproliferative effects in MCF-7 cells of phenolic analogues of trioxifene, [3,4-dihydro-2-(4- methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]- phenyl]methanone.
Year : 1992
Volume : 35
Issue : 5
First Page : 931
Last Page : 938
Authors : Jones CD, Blaszczak LC, Goettel ME, Suarez T, Crowell TA, Mabry TE, Ruenitz PC, Srivatsan V.
Abstract : Benzothiophenes 3 and 4, derived from the acrylophenone antiestrogen trioxifene (2), are characterized by high estrogen receptor (ER) affinity and low residual estrogenicity compared to tamoxifen (1a). In order to characterize further the growth suppression mechanism for these structural types we have prepared structural variants of 2 bearing hydroxy groups positioned to maximize ER affinity. Thus, dihydronaphthalenes 5 and 6 and benzofluorenes 7 and 8 were prepared and studied in MCF-7 human breast cancer cells, in comparison with 3 and 4. All compounds were powerful suppressants of cell growth, with 50% inhibition ranging from 4.5 to 160 nM. Greatest potency was seen with diphenols 6 and 8. These compounds had intracellular ER affinities ranging from 0.2 to 4.1% of that of estradiol, suggestive of a potential for partial agonist effects. Simultaneous exposure of cells to 0.1 microM concentrations of estradiol and 3 or 4 did not affect the degree of growth inhibition seen with 0.1 microM 3 or 4 alone. Partial reversal of inhibition occurred when 0.1 microM 5-8 were each accompanied by 0.1 microM estradiol. Under these conditions complete reversal of growth inhibition has been found with 1a, 1b, and other triarylethylenes. Calmodulin, a putative target for triarylethylenes, and which is antagonized by 1a, was shown to interact weakly with 7 and 8 and not at all with 3-6. These results suggest that MCF-7 cell growth suppression by 3-8 may be due to interaction with unidentified receptors besides ER and extend earlier findings indicating that events occurring after interaction of these compounds with ER differ from those of triarylethylene antiestrogens.
|
Displacement of [3H]17-beta-estradiol from Estrogen receptor of rabbit uterine tissue
|
Oryctolagus cuniculus
|
7.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel thio-substituted chromanes as high-affinity partial agonists for the estrogen receptor.
Year : 2002
Volume : 12
Issue : 1
First Page : 17
Last Page : 19
Authors : Christiansen LB, Wenckens M, Bury PS, Gissel B, Hansen BS, Thorpe SM, Jacobsen P, Kanstrup A, Jørgensen AS, Naerum L, Wassermann K.
Abstract : Synthesis of (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-piperidinoethanethio)phenyl)chromane (13) and (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethanethio)phenyl)chromane (15) is presented. These compounds are representatives of a novel class of compounds with high in vitro binding affinity for the estrogen receptor (IC(50)=7-10 nM), and very low in vitro uterotrophic activity (max stim.=5-17% rel to moxestrol; EC(50)=0.5-1.8 nM).
|
Inhibition of estradiol binding to estrogen receptor
|
Rattus norvegicus
|
1.85
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene.
Year : 1998
Volume : 41
Issue : 16
First Page : 2928
Last Page : 2931
Authors : Rosati RL, Da Silva Jardine P, Cameron KO, Thompson DD, Ke HZ, Toler SM, Brown TA, Pan LC, Ebbinghaus CF, Reinhold AR, Elliott NC, Newhouse BN, Tjoa CM, Sweetnam PM, Cole MJ, Arriola MW, Gauthier JW, Crawford DT, Nickerson DF, Pirie CM, Qi H, Simmons HA, Tkalcevic GT.
|
Binding affinity for Human Estrogen receptor-alpha
|
Homo sapiens
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Phenylspiroindenes: a novel class of selective estrogen receptor modulators (SERMs).
Year : 2003
Volume : 13
Issue : 3
First Page : 479
Last Page : 483
Authors : Blizzard TA, Morgan JD, Mosley RT, Birzin ET, Frisch K, Rohrer SP, Hammond ML.
Abstract : A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to raloxifene (1) as an estrogen receptor ligand.
|
In vitro inhibition of [3H]17-beta-estradiol binding to human estrogen receptor alpha
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens.
Year : 2001
Volume : 44
Issue : 11
First Page : 1654
Last Page : 1657
Authors : Miller CP, Collini MD, Tran BD, Harris HA, Kharode YP, Marzolf JT, Moran RA, Henderson RA, Bender RH, Unwalla RJ, Greenberger LM, Yardley JP, Abou-Gharbia MA, Lyttle CR, Komm BS.
|
Binding affinity for Rat Estrogen receptor-alpha
|
Rattus norvegicus
|
0.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Phenylspiroindenes: a novel class of selective estrogen receptor modulators (SERMs).
Year : 2003
Volume : 13
Issue : 3
First Page : 479
Last Page : 483
Authors : Blizzard TA, Morgan JD, Mosley RT, Birzin ET, Frisch K, Rohrer SP, Hammond ML.
Abstract : A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to raloxifene (1) as an estrogen receptor ligand.
|
Binding affinity for Human Estrogen receptor-beta
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Phenylspiroindenes: a novel class of selective estrogen receptor modulators (SERMs).
Year : 2003
Volume : 13
Issue : 3
First Page : 479
Last Page : 483
Authors : Blizzard TA, Morgan JD, Mosley RT, Birzin ET, Frisch K, Rohrer SP, Hammond ML.
Abstract : A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to raloxifene (1) as an estrogen receptor ligand.
|
In vitro inhibition of 1 nM 17-beta-estradiol induced transcriptional activation in T47D cells expressing estrogen receptor beta
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.
Year : 2002
Volume : 45
Issue : 25
First Page : 5492
Last Page : 5505
Authors : Henke BR, Consler TG, Go N, Hale RL, Hohman DR, Jones SA, Lu AT, Moore LB, Moore JT, Orband-Miller LA, Robinett RG, Shearin J, Spearing PK, Stewart EL, Turnbull PS, Weaver SL, Williams SP, Wisely GB, Lambert MH.
Abstract : A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.
|
Percent maximal inhibition of 1 nM 17-beta-estradiol induced transcriptional activation in T47D cells expressing estrogen receptor beta
|
Homo sapiens
|
120.0
%
|
|
Journal : J. Med. Chem.
Title : A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.
Year : 2002
Volume : 45
Issue : 25
First Page : 5492
Last Page : 5505
Authors : Henke BR, Consler TG, Go N, Hale RL, Hohman DR, Jones SA, Lu AT, Moore LB, Moore JT, Orband-Miller LA, Robinett RG, Shearin J, Spearing PK, Stewart EL, Turnbull PS, Weaver SL, Williams SP, Wisely GB, Lambert MH.
Abstract : A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.
|
In vitro inhibitory concentration against [3H]17-beta-estradiol binding to human estrogen receptor 2
|
Homo sapiens
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens.
Year : 2001
Volume : 44
Issue : 11
First Page : 1654
Last Page : 1657
Authors : Miller CP, Collini MD, Tran BD, Harris HA, Kharode YP, Marzolf JT, Moran RA, Henderson RA, Bender RH, Unwalla RJ, Greenberger LM, Yardley JP, Abou-Gharbia MA, Lyttle CR, Komm BS.
|
Binding affinity foor Rat Estrogen receptor-beta
|
Rattus norvegicus
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Phenylspiroindenes: a novel class of selective estrogen receptor modulators (SERMs).
Year : 2003
Volume : 13
Issue : 3
First Page : 479
Last Page : 483
Authors : Blizzard TA, Morgan JD, Mosley RT, Birzin ET, Frisch K, Rohrer SP, Hammond ML.
Abstract : A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to raloxifene (1) as an estrogen receptor ligand.
|
Inhibition of [3H]17-beta-estradiol binding to human recombinant Estrogen receptor alpha.
|
None
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward selective ERbeta agonists for central nervous system disorders: synthesis and characterization of aryl benzthiophenes.
Year : 2002
Volume : 45
Issue : 7
First Page : 1399
Last Page : 1401
Authors : Schopfer U, Schoeffter P, Bischoff SF, Nozulak J, Feuerbach D, Floersheim P.
Abstract : In an effort to identify selective ligands for the estrogen receptor subtype ERbeta, a series of aryl benzthiophenes was synthesized. In a radioligand binding assay and reporter gene assays in HeLa and SH-SY5Y cells, compounds were characterized as ERbeta-selective agonists. By targeting ERbeta in the brain, these compounds could lead to drugs able to separate the beneficial effects of estrogens on mood, learning, and memory from side effects such as the stimulation of endometrial and breast cancer.
|
Displacement of [3H]17-beta-estradiol from full length human estrogen receptor alpha
|
None
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 4: The SAR of the syn-dihydrobenzoxathiin SERAMs.
Year : 2004
Volume : 14
Issue : 11
First Page : 2741
Last Page : 2745
Authors : Kim S, Wu J, Chen HY, Birzin ET, Chan W, Yang YT, Colwell L, Li S, Dahllund J, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of estrogen receptor ligands based on a dihydrobenzoxathiin scaffold is described and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. The most active analogue, 22, was found to be 40-fold ERalpha selective in a competitive binding assay, and 22 demonstrated very potent in vivo antagonism of estradiol driven proliferation in an immature rat uterine weight gain assay.
|
Binding affinity against human estrogen receptor alpha in competitive binding assay
|
None
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 1: The discovery of flavanoids with subtype selectivity.
Year : 2004
Volume : 14
Issue : 6
First Page : 1417
Last Page : 1421
Authors : Chen HY, Dykstra KD, Birzin ET, Frisch K, Chan W, Yang YT, Mosley RT, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A class of flavanoids exhibiting a high degree of selectivity for ERalpha over ERbeta has been discovered. The most active analogue 6 was found to be 66-fold ERalpha-selective and demonstrated uterine estradiol antagonism.
|
Binding affinity towards human estrogen receptor alpha
|
None
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 3: The SAR of dihydrobenzoxathiin SERMs.
Year : 2004
Volume : 14
Issue : 10
First Page : 2551
Last Page : 2554
Authors : Chen HY, Kim S, Wu JY, Birzin ET, Chan W, Yang YT, Dahllund J, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of 3-alkyl, 3-cycloalkyl, and 3-heteroaryl dihydrobenzoxathiin analogs 1 were prepared and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. In general, the compounds were found to exhibit a high degree of selectivity for ER alpha over ER beta, but were less potent than the original lead compound 1a in the inhibition of estradiol-driven uterine proliferation.
|
Binding affinity towards human recombinant Estrogen receptor alpha was determined
|
None
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor alpha modulators.
Year : 2004
Volume : 47
Issue : 9
First Page : 2171
Last Page : 2175
Authors : Kim S, Wu JY, Birzin ET, Frisch K, Chan W, Pai LY, Yang YT, Mosley RT, Fitzgerald PM, Sharma N, Dahllund J, Thorsell AG, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.
|
In vitro binding affinity for estrogen receptor alpha
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel estrogen receptor ligand template.
Year : 2003
Volume : 13
Issue : 11
First Page : 1919
Last Page : 1922
Authors : Sibley R, Hatoum-Mokdad H, Schoenleber R, Musza L, Stirtan W, Marrero D, Carley W, Xiao H, Dumas J.
Abstract : Three synthetic routes towards a novel estrogen receptor ligand template based on a rigid bicyclo-[3.3.1]-nonene core have been investigated. The prototype compound exhibits potent binding at the ERbeta receptor and promising estrogen receptor subtype selectivity.
|
In vitro inhibition of transcriptional activation induced by 1 nM 17-beta estradiol in T47D cells expressing estrogen receptor alpha
|
Homo sapiens
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.
Year : 2002
Volume : 45
Issue : 25
First Page : 5492
Last Page : 5505
Authors : Henke BR, Consler TG, Go N, Hale RL, Hohman DR, Jones SA, Lu AT, Moore LB, Moore JT, Orband-Miller LA, Robinett RG, Shearin J, Spearing PK, Stewart EL, Turnbull PS, Weaver SL, Williams SP, Wisely GB, Lambert MH.
Abstract : A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.
|
Percent maximal inhibition of transcriptional activation stimulated by 1 nM 17 beta-estradiol in T47D cells expressing estrogen receptor alpha
|
Homo sapiens
|
113.0
%
|
|
Journal : J. Med. Chem.
Title : A new series of estrogen receptor modulators that display selectivity for estrogen receptor beta.
Year : 2002
Volume : 45
Issue : 25
First Page : 5492
Last Page : 5505
Authors : Henke BR, Consler TG, Go N, Hale RL, Hohman DR, Jones SA, Lu AT, Moore LB, Moore JT, Orband-Miller LA, Robinett RG, Shearin J, Spearing PK, Stewart EL, Turnbull PS, Weaver SL, Williams SP, Wisely GB, Lambert MH.
Abstract : A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.
|
Ability to displace [3H]17-beta-estradiol from Estrogen receptor alpha by scintillation proximity assay.
|
None
|
0.22
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Amino-4,6-diarylpyridines as novel ligands for the estrogen receptor.
Year : 2001
Volume : 11
Issue : 14
First Page : 1939
Last Page : 1942
Authors : Henke BR, Drewry DH, Jones SA, Stewart EL, Weaver SL, Wiethe RW.
Abstract : We have prepared a novel series of 2-amino-4,6-diarylpyridines that function as ligands of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). These compounds bind to both ERalpha and ERbeta with a modest selectivity for the alpha subtype. The most potent of these analogues, compound 19, has a K(i)=20nM at ERalpha. These molecules represent a novel template for designing potentially useful ligands for the estrogen receptor.
|
Binding affinity for estrogen receptor alpha
|
Homo sapiens
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tetrahydroquinoline-based selective estrogen receptor modulators (SERMs).
Year : 2003
Volume : 13
Issue : 11
First Page : 1907
Last Page : 1910
Authors : Wallace OB, Lauwers KS, Jones SA, Dodge JA.
Abstract : A new series of estrogen receptor ligands based on a 6-hydroxy-tetrahydroquinoline scaffold is described, in addition to their binding affinity and functional activity in MCF-7 cells. Several 1,2-disubstituted tetrahydroquinolines bearing a basic side chain were shown to be high affinity ligands and antagonists in the MCF-7 proliferation assay. Compounds lacking the basic side chain were agonists in the MCF-7 assay.
|
Inhibition of [3H]17-beta-estradiol binding to human recombinant Estrogen receptor beta.
|
None
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward selective ERbeta agonists for central nervous system disorders: synthesis and characterization of aryl benzthiophenes.
Year : 2002
Volume : 45
Issue : 7
First Page : 1399
Last Page : 1401
Authors : Schopfer U, Schoeffter P, Bischoff SF, Nozulak J, Feuerbach D, Floersheim P.
Abstract : In an effort to identify selective ligands for the estrogen receptor subtype ERbeta, a series of aryl benzthiophenes was synthesized. In a radioligand binding assay and reporter gene assays in HeLa and SH-SY5Y cells, compounds were characterized as ERbeta-selective agonists. By targeting ERbeta in the brain, these compounds could lead to drugs able to separate the beneficial effects of estrogens on mood, learning, and memory from side effects such as the stimulation of endometrial and breast cancer.
|
Displacement of [3H]17-beta-estradiol from full length human estrogen receptor beta
|
None
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 4: The SAR of the syn-dihydrobenzoxathiin SERAMs.
Year : 2004
Volume : 14
Issue : 11
First Page : 2741
Last Page : 2745
Authors : Kim S, Wu J, Chen HY, Birzin ET, Chan W, Yang YT, Colwell L, Li S, Dahllund J, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of estrogen receptor ligands based on a dihydrobenzoxathiin scaffold is described and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. The most active analogue, 22, was found to be 40-fold ERalpha selective in a competitive binding assay, and 22 demonstrated very potent in vivo antagonism of estradiol driven proliferation in an immature rat uterine weight gain assay.
|
Binding affinity against human estrogen receptor beta (ER beta) in competitive binding assay
|
None
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 1: The discovery of flavanoids with subtype selectivity.
Year : 2004
Volume : 14
Issue : 6
First Page : 1417
Last Page : 1421
Authors : Chen HY, Dykstra KD, Birzin ET, Frisch K, Chan W, Yang YT, Mosley RT, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A class of flavanoids exhibiting a high degree of selectivity for ERalpha over ERbeta has been discovered. The most active analogue 6 was found to be 66-fold ERalpha-selective and demonstrated uterine estradiol antagonism.
|
Binding affinity towards human estrogen receptor beta (ERbeta)
|
None
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 3: The SAR of dihydrobenzoxathiin SERMs.
Year : 2004
Volume : 14
Issue : 10
First Page : 2551
Last Page : 2554
Authors : Chen HY, Kim S, Wu JY, Birzin ET, Chan W, Yang YT, Dahllund J, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of 3-alkyl, 3-cycloalkyl, and 3-heteroaryl dihydrobenzoxathiin analogs 1 were prepared and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. In general, the compounds were found to exhibit a high degree of selectivity for ER alpha over ER beta, but were less potent than the original lead compound 1a in the inhibition of estradiol-driven uterine proliferation.
|
Binding affinity towards human recombinant Estrogen receptor beta was determined
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor alpha modulators.
Year : 2004
Volume : 47
Issue : 9
First Page : 2171
Last Page : 2175
Authors : Kim S, Wu JY, Birzin ET, Frisch K, Chan W, Pai LY, Yang YT, Mosley RT, Fitzgerald PM, Sharma N, Dahllund J, Thorsell AG, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.
|
In vitro binding affinity for estrogen receptor beta
|
Homo sapiens
|
470.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel estrogen receptor ligand template.
Year : 2003
Volume : 13
Issue : 11
First Page : 1919
Last Page : 1922
Authors : Sibley R, Hatoum-Mokdad H, Schoenleber R, Musza L, Stirtan W, Marrero D, Carley W, Xiao H, Dumas J.
Abstract : Three synthetic routes towards a novel estrogen receptor ligand template based on a rigid bicyclo-[3.3.1]-nonene core have been investigated. The prototype compound exhibits potent binding at the ERbeta receptor and promising estrogen receptor subtype selectivity.
|
Ability to displace [3H]17-beta-estradiol from Estrogen receptor beta by scintillation proximity assay.
|
None
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Amino-4,6-diarylpyridines as novel ligands for the estrogen receptor.
Year : 2001
Volume : 11
Issue : 14
First Page : 1939
Last Page : 1942
Authors : Henke BR, Drewry DH, Jones SA, Stewart EL, Weaver SL, Wiethe RW.
Abstract : We have prepared a novel series of 2-amino-4,6-diarylpyridines that function as ligands of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). These compounds bind to both ERalpha and ERbeta with a modest selectivity for the alpha subtype. The most potent of these analogues, compound 19, has a K(i)=20nM at ERalpha. These molecules represent a novel template for designing potentially useful ligands for the estrogen receptor.
|
Binding affinity for estrogen receptor beta
|
Homo sapiens
|
4.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tetrahydroquinoline-based selective estrogen receptor modulators (SERMs).
Year : 2003
Volume : 13
Issue : 11
First Page : 1907
Last Page : 1910
Authors : Wallace OB, Lauwers KS, Jones SA, Dodge JA.
Abstract : A new series of estrogen receptor ligands based on a 6-hydroxy-tetrahydroquinoline scaffold is described, in addition to their binding affinity and functional activity in MCF-7 cells. Several 1,2-disubstituted tetrahydroquinolines bearing a basic side chain were shown to be high affinity ligands and antagonists in the MCF-7 proliferation assay. Compounds lacking the basic side chain were agonists in the MCF-7 assay.
|
Binding to Estrogen receptor- alpha (ER alpha) receptor
|
None
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Solid-phase synthesis and investigation of benzofurans as selective estrogen receptor modulators.
Year : 2002
Volume : 12
Issue : 20
First Page : 2875
Last Page : 2878
Authors : Smith RA, Chen J, Mader MM, Muegge I, Moehler U, Katti S, Marrero D, Stirtan WG, Weaver DR, Xiao H, Carley W.
Abstract : A library of benzofurans was prepared by solid-phase synthesis methods, and several analogues were identified as potent ligands for the estrogen receptors ER-alpha and ER-beta, with some compounds having selectivity for ER-alpha. Analogues designed to more closely mimic Raloxifene were less effective. Certain benzofurans were effective in a bone pit assay, but were characterized as agonists in a MCF-7 breast tumor cell proliferation assay.
|
Binding to Estrogen receptor- beta (ER beta) receptor
|
None
|
470.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Solid-phase synthesis and investigation of benzofurans as selective estrogen receptor modulators.
Year : 2002
Volume : 12
Issue : 20
First Page : 2875
Last Page : 2878
Authors : Smith RA, Chen J, Mader MM, Muegge I, Moehler U, Katti S, Marrero D, Stirtan WG, Weaver DR, Xiao H, Carley W.
Abstract : A library of benzofurans was prepared by solid-phase synthesis methods, and several analogues were identified as potent ligands for the estrogen receptors ER-alpha and ER-beta, with some compounds having selectivity for ER-alpha. Analogues designed to more closely mimic Raloxifene were less effective. Certain benzofurans were effective in a bone pit assay, but were characterized as agonists in a MCF-7 breast tumor cell proliferation assay.
|
In vivo inhibition of human ERalpha/ERbeta co-expressed in HEK 293 cells; 4/60
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 3: The SAR of dihydrobenzoxathiin SERMs.
Year : 2004
Volume : 14
Issue : 10
First Page : 2551
Last Page : 2554
Authors : Chen HY, Kim S, Wu JY, Birzin ET, Chan W, Yang YT, Dahllund J, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of 3-alkyl, 3-cycloalkyl, and 3-heteroaryl dihydrobenzoxathiin analogs 1 were prepared and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. In general, the compounds were found to exhibit a high degree of selectivity for ER alpha over ER beta, but were less potent than the original lead compound 1a in the inhibition of estradiol-driven uterine proliferation.
|
Antagonist effect in breast tissue was assayed by inhibition of estrogen stimulated MCF-7 cell proliferation
|
None
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Versatile raloxifene triflates
Year : 1997
Volume : 7
Issue : 7
First Page : 887
Last Page : 892
Authors : Martin MJ, Grese TA, Glasebrook AL, Matsumoto K, Pennington LD, Phillips D, Short LL
|
Inhibition of estrogen-stimulated MCF-7 cell proliferation
|
Homo sapiens
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacology of conformationally restricted raloxifene analogues: highly potent selective estrogen receptor modulators.
Year : 1998
Volume : 41
Issue : 8
First Page : 1272
Last Page : 1283
Authors : Grese TA, Pennington LD, Sluka JP, Adrian MD, Cole HW, Fuson TR, Magee DE, Phillips DL, Rowley ER, Shetler PK, Short LL, Venugopalan M, Yang NN, Sato M, Glasebrook AL, Bryant HU.
Abstract : The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator (SERM) which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. In vivo structure-activity relationships and molecular modeling studies have indicated that the orientation of the basic amine-containing side chain of 1, relative to the stilbene plane, is an important discriminating factor for the maintenance of tissue selectivity. We have constructed a series of analogues of 1 in which this side chain is held in an orientation which is orthogonal to the stilbene plane, similar to the low-energy conformation predicted for raloxifene. Herein, we report on the synthesis of these compounds and on their activity in a series of in vitro and in vivo biological assays reflective of the SERM profile. In particular, we describe their ability to (1) bind the estrogen receptor, (2) antagonize estrogen-stimulated proliferation of MCF-7 cells in vitro, (3) stimulate TGF-beta3 gene expression in cell culture, (4) inhibit the uterine effects of ethynyl estradiol in immature rats, and (5) potently reduce serum cholesterol and protect against osteopenia in ovariectomized (OVX) rats without estrogen-like stimulation of uterine tissue. These data demonstrate that one of these compounds, LY357489,4, is among the most potent SERMs described to date with in vivo efficacy on bone and cholesterol metabolism in OVX rats at doses as low as 0.01 mg/kg/d.
|
In vitro inhibition of estrogen-stimulated MCF-7 cell proliferation
|
Homo sapiens
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel nonsteroidal selective estrogen receptor modulators. Carbon and heteroatom replacement of oxygen in the ethoxypiperidine region of raloxifene.
Year : 1999
Volume : 9
Issue : 4
First Page : 523
Last Page : 528
Authors : Schmid CR, Sluka JP, Duke KM, Glasebrook AW.
Abstract : Compounds were synthesized where oxygen in the ethoxypiperidine region of raloxifene is replaced with carbon, sulfur, or nitrogen linkages. Thia- and aza-substituted compounds were prepared by novel methodology. The compounds were evaluated in vitro as selective estrogen receptor modulators (SERMs). Calculations suggested the compounds exhibit an ER-alpha binding affinity/conformational energy relationship.
|
Inhibition of estradiol-stimulated MCF-7 breast adenocarcinoma cell proliferation
|
Homo sapiens
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tetrahydroquinoline-based selective estrogen receptor modulators (SERMs).
Year : 2003
Volume : 13
Issue : 11
First Page : 1907
Last Page : 1910
Authors : Wallace OB, Lauwers KS, Jones SA, Dodge JA.
Abstract : A new series of estrogen receptor ligands based on a 6-hydroxy-tetrahydroquinoline scaffold is described, in addition to their binding affinity and functional activity in MCF-7 cells. Several 1,2-disubstituted tetrahydroquinolines bearing a basic side chain were shown to be high affinity ligands and antagonists in the MCF-7 proliferation assay. Compounds lacking the basic side chain were agonists in the MCF-7 assay.
|
In vitro antagonist effect on estrogen receptor alpha transcriptional activation in MCF-7 cells against 10 pM 17-beta-estradiol
|
Homo sapiens
|
0.72
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens.
Year : 2001
Volume : 44
Issue : 11
First Page : 1654
Last Page : 1657
Authors : Miller CP, Collini MD, Tran BD, Harris HA, Kharode YP, Marzolf JT, Moran RA, Henderson RA, Bender RH, Unwalla RJ, Greenberger LM, Yardley JP, Abou-Gharbia MA, Lyttle CR, Komm BS.
|
Antagonism of estrogen action in a mammary tumor cell line was assayed via inhibition of MCF-7 cell proliferation stimulated by 10 e-11 M 17-beta-estradiol (in vitro)
|
None
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of selective estrogen receptor modulators: modifications to the 2-arylbenzothiophene core of raloxifene.
Year : 1997
Volume : 40
Issue : 2
First Page : 146
Last Page : 167
Authors : Grese TA, Cho S, Finley DR, Godfrey AG, Jones CD, Lugar CW, Martin MJ, Matsumoto K, Pennington LD, Winter MA, Adrian MD, Cole HW, Magee DE, Phillips DL, Rowley ER, Short LL, Glasebrook AL, Bryant HU.
Abstract : The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.
|
Antiproliferative activity against MCF-7 cell line
|
Homo sapiens
|
4.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Lead identification of a potent benzopyranone selective estrogen receptor modulator.
Year : 2004
Volume : 14
Issue : 13
First Page : 3407
Last Page : 3410
Authors : McKie JA, Bhagwat SS, Brady H, Doubleday M, Gayo L, Hickman M, Jalluri RK, Khammungkhune S, Kois A, Mortensen D, Richard N, Sapienza J, Shevlin G, Stein B, Sutherland M.
Abstract : Starting from a phenol screening hit (6), three series of benzopyranone selective estrogen receptor modulators (SERMs) have been designed, synthesized, and analyzed for both estrogen receptor alpha binding affinity and in vitro activity in two cell assays. The lead compound identified, SP500263 (13), was more potent than raloxifene and tamoxifen in a cell-based assay measuring inhibition of interleukin-6 release.
|
Inhibition of 17-beta-estradiol (10e-11 M) mediated MCF-7 cell proliferation
|
Homo sapiens
|
0.34
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of trans-2,3-dihydroraloxifene.
Year : 1999
Volume : 9
Issue : 8
First Page : 1137
Last Page : 1140
Authors : Schmid CR, Glasebrook AL, Misner JW, Stephenson GA.
Abstract : The synthesis and biological evaluation of trans-2,3-dihydroraloxifene, 2, is described. The synthesis proceeds in 8 steps in 20% overall yield. Relative trans 2,3-stereochemistry is definitively established in ester 6, which is converted to the title compound via derivatization, Grignard addition, and deprotection. Evaluation in vitro shows the compound to be a potent selective estrogen receptor modulator (SERM).
|
Anti-estrogenic activity as percent inhibition/control in uterotrophic assay on co-administration with subcutaneous 17-beta-estradiol in rats; 96/8
|
Rattus norvegicus
|
96.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 3: The SAR of dihydrobenzoxathiin SERMs.
Year : 2004
Volume : 14
Issue : 10
First Page : 2551
Last Page : 2554
Authors : Chen HY, Kim S, Wu JY, Birzin ET, Chan W, Yang YT, Dahllund J, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of 3-alkyl, 3-cycloalkyl, and 3-heteroaryl dihydrobenzoxathiin analogs 1 were prepared and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. In general, the compounds were found to exhibit a high degree of selectivity for ER alpha over ER beta, but were less potent than the original lead compound 1a in the inhibition of estradiol-driven uterine proliferation.
|
In vivo estrogenic activity in immature rat uterine weight assay at 0.6 mg/kg subcutaneous dose
|
Rattus norvegicus
|
96.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 1: The discovery of flavanoids with subtype selectivity.
Year : 2004
Volume : 14
Issue : 6
First Page : 1417
Last Page : 1421
Authors : Chen HY, Dykstra KD, Birzin ET, Frisch K, Chan W, Yang YT, Mosley RT, DiNinno F, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A class of flavanoids exhibiting a high degree of selectivity for ERalpha over ERbeta has been discovered. The most active analogue 6 was found to be 66-fold ERalpha-selective and demonstrated uterine estradiol antagonism.
|
Ability to inhibit release of interleukin-6 from U2OS cell lines transfected with estrogen receptor alpha
|
Homo sapiens
|
3.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Lead identification of a potent benzopyranone selective estrogen receptor modulator.
Year : 2004
Volume : 14
Issue : 13
First Page : 3407
Last Page : 3410
Authors : McKie JA, Bhagwat SS, Brady H, Doubleday M, Gayo L, Hickman M, Jalluri RK, Khammungkhune S, Kois A, Mortensen D, Richard N, Sapienza J, Shevlin G, Stein B, Sutherland M.
Abstract : Starting from a phenol screening hit (6), three series of benzopyranone selective estrogen receptor modulators (SERMs) have been designed, synthesized, and analyzed for both estrogen receptor alpha binding affinity and in vitro activity in two cell assays. The lead compound identified, SP500263 (13), was more potent than raloxifene and tamoxifen in a cell-based assay measuring inhibition of interleukin-6 release.
|
Affinity for ERG2 of Saccharomyces cerevisiae using [3H]ifenprodil or (+)-[3H]pentazocine radioligand
|
Saccharomyces cerevisiae
|
66.0
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.
|
Affinity for sigma receptor type 1 of guinea pig using [3H]ifenprodil or (+)-[3H]pentazocine radioligand
|
Cavia porcellus
|
38.0
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.
|
Affinity for human EMP expressed in ERG2 deficient strain of Saccharomyces cerevisiae using [3H]ifenprodil or (+)-[3H]pentazocine as radioligand
|
Homo sapiens
|
1.0
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.
|
Binding potency for human ER beta
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 7: Dihydrobenzoxathiin SERAMs with bicyclic amine side chains.
Year : 2004
Volume : 14
Issue : 15
First Page : 3861
Last Page : 3864
Authors : Blizzard TA, DiNinno F, Morgan JD, Chen HY, Wu JY, Gude C, Kim S, Chan W, Birzin ET, Tien Yang Y, Pai LY, Zhang Z, Hayes EC, DaSilva CA, Tang W, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of benzoxathiin SERAMs with bicyclic amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
|
Binding potency for human ER beta
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 8: Dihydrobenzoxathiin SERAMs with heteroatom-substituted side chains.
Year : 2004
Volume : 14
Issue : 15
First Page : 3865
Last Page : 3868
Authors : Blizzard TA, DiNinno F, Morgan JD, Wu JY, Chen HY, Kim S, Chan W, Birzin ET, Yang YT, Pai LY, Zhang Z, Hayes EC, DaSilva CA, Tang W, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of benzoxathiin SERAMs with heteroatom-substituted amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
|
Binding potency for human ER alpha
|
Homo sapiens
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 7: Dihydrobenzoxathiin SERAMs with bicyclic amine side chains.
Year : 2004
Volume : 14
Issue : 15
First Page : 3861
Last Page : 3864
Authors : Blizzard TA, DiNinno F, Morgan JD, Chen HY, Wu JY, Gude C, Kim S, Chan W, Birzin ET, Tien Yang Y, Pai LY, Zhang Z, Hayes EC, DaSilva CA, Tang W, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of benzoxathiin SERAMs with bicyclic amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
|
Binding potency for human ER alpha
|
Homo sapiens
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 8: Dihydrobenzoxathiin SERAMs with heteroatom-substituted side chains.
Year : 2004
Volume : 14
Issue : 15
First Page : 3865
Last Page : 3868
Authors : Blizzard TA, DiNinno F, Morgan JD, Wu JY, Chen HY, Kim S, Chan W, Birzin ET, Yang YT, Pai LY, Zhang Z, Hayes EC, DaSilva CA, Tang W, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of benzoxathiin SERAMs with heteroatom-substituted amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
|
Inhibition of estrogen receptor beta
|
Homo sapiens
|
18.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzothiophenes containing a piperazine side chain as selective ligands for the estrogen receptor alpha and their bioactivities in vivo.
Year : 2005
Volume : 15
Issue : 5
First Page : 1505
Last Page : 1507
Authors : Yang C, Xu G, Li J, Wu X, Liu B, Yan X, Wang M, Xie Y.
Abstract : The synthesis of benzothiophenes containing a piperazine side chain and their binding affinities for estrogen receptors are described. These compounds bearing piperazine side chains were identified to be high-affinity ligands with high selectivity for ER alpha subtype. They were also potent agonists in bone tissue.
|
Inhibition of estrogen receptor alpha
|
Homo sapiens
|
0.73
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzothiophenes containing a piperazine side chain as selective ligands for the estrogen receptor alpha and their bioactivities in vivo.
Year : 2005
Volume : 15
Issue : 5
First Page : 1505
Last Page : 1507
Authors : Yang C, Xu G, Li J, Wu X, Liu B, Yan X, Wang M, Xie Y.
Abstract : The synthesis of benzothiophenes containing a piperazine side chain and their binding affinities for estrogen receptors are described. These compounds bearing piperazine side chains were identified to be high-affinity ligands with high selectivity for ER alpha subtype. They were also potent agonists in bone tissue.
|
Inhibition of [3H]17-beta-estradiol binding to human estrogen receptor beta
|
Homo sapiens
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzothieno[3,2-b]indole derivatives as potent selective estrogen receptor modulators.
Year : 2005
Volume : 15
Issue : 11
First Page : 2891
Last Page : 2893
Authors : Ji Q, Gao J, Wang J, Yang C, Hui X, Yan X, Wu X, Xie Y, Wang MW.
Abstract : A series of estrogen receptor ligands based on benzothieno[3,2-b]indole were synthesized and their binding affinity for estrogen receptor subtypes (ERalpha and ERbeta) and effects on mouse uterus and bone were evaluated. Some of these compounds showed strong binding affinity to ER and significantly increased the bone mineral density of ovariectomized mice.
|
Inhibition of [3H]17-beta-estradiol binding to human estrogen receptor alpha
|
Homo sapiens
|
0.89
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzothieno[3,2-b]indole derivatives as potent selective estrogen receptor modulators.
Year : 2005
Volume : 15
Issue : 11
First Page : 2891
Last Page : 2893
Authors : Ji Q, Gao J, Wang J, Yang C, Hui X, Yan X, Wu X, Xie Y, Wang MW.
Abstract : A series of estrogen receptor ligands based on benzothieno[3,2-b]indole were synthesized and their binding affinity for estrogen receptor subtypes (ERalpha and ERbeta) and effects on mouse uterus and bone were evaluated. Some of these compounds showed strong binding affinity to ER and significantly increased the bone mineral density of ovariectomized mice.
|
Inhibition of binding to recombinant human estrogen receptor beta
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 9: Dihydrobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers.
Year : 2005
Volume : 15
Issue : 1
First Page : 107
Last Page : 113
Authors : Blizzard TA, Dininno F, Morgan JD, Chen HY, Wu JY, Kim S, Chan W, Birzin ET, Yang YT, Pai LY, Fitzgerald PM, Sharma N, Li Y, Zhang Z, Hayes EC, Dasilva CA, Tang W, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
|
Inhibition of bindign to recombinant human estrogen receptor alpha
|
Homo sapiens
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 9: Dihydrobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers.
Year : 2005
Volume : 15
Issue : 1
First Page : 107
Last Page : 113
Authors : Blizzard TA, Dininno F, Morgan JD, Chen HY, Wu JY, Kim S, Chan W, Birzin ET, Yang YT, Pai LY, Fitzgerald PM, Sharma N, Li Y, Zhang Z, Hayes EC, Dasilva CA, Tang W, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
|
Inhibition of [3H]estradiol binding to human estrogen receptor beta expressed in HeLa cells
|
Homo sapiens
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands.
Year : 2005
Volume : 48
Issue : 2
First Page : 364
Last Page : 379
Authors : Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P.
Abstract : We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
|
Inhibition of [3H]estradiol binding to human estrogen receptor alpha expressed in HeLa cells
|
Homo sapiens
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands.
Year : 2005
Volume : 48
Issue : 2
First Page : 364
Last Page : 379
Authors : Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P.
Abstract : We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
|
Inhibition of human estrogen receptor 2 using tritiated estradiol incubated for 3 hr
|
Homo sapiens
|
1.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 13: Dihydrobenzoxathiin SERAMs with an optimized antagonist side chain.
Year : 2005
Volume : 15
Issue : 17
First Page : 3912
Last Page : 3916
Authors : Blizzard TA, DiNinno F, Chen HY, Kim S, Wu JY, Chan W, Birzin ET, Yang YT, Pai LY, Hayes EC, DaSilva CA, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : An optimized side chain for dihydrobenzoxathiin SERAMs was discovered and attached to four dihydrobenzoxathiin platforms. The novel SERAMs show exceptional estrogen antagonist activity in uterine tissue and an MCF-7 breast cancer cell assay.
|
Inhibition of 17-beta-estradiol mediated luciferase transcription in HeLa cells expressing human estrogen receptor beta; ERE assay
|
Homo sapiens
|
341.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands.
Year : 2005
Volume : 48
Issue : 2
First Page : 364
Last Page : 379
Authors : Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P.
Abstract : We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
|
Inhibition of 17-beta-estradiol mediated luciferase transcription in HeLa cells expressing human estrogen receptor alpha; ERE assay
|
Homo sapiens
|
2.4
nM
|
|
Journal : J. Med. Chem.
Title : Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands.
Year : 2005
Volume : 48
Issue : 2
First Page : 364
Last Page : 379
Authors : Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P.
Abstract : We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
|
In vitro antagonistic activity against MCF-7 cells was tested using proliferation assay
|
Homo sapiens
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 7: Dihydrobenzoxathiin SERAMs with bicyclic amine side chains.
Year : 2004
Volume : 14
Issue : 15
First Page : 3861
Last Page : 3864
Authors : Blizzard TA, DiNinno F, Morgan JD, Chen HY, Wu JY, Gude C, Kim S, Chan W, Birzin ET, Tien Yang Y, Pai LY, Zhang Z, Hayes EC, DaSilva CA, Tang W, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of benzoxathiin SERAMs with bicyclic amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
|
In vitro antagonistic activity against MCF-7 cells was tested using proliferation assay
|
Homo sapiens
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 8: Dihydrobenzoxathiin SERAMs with heteroatom-substituted side chains.
Year : 2004
Volume : 14
Issue : 15
First Page : 3865
Last Page : 3868
Authors : Blizzard TA, DiNinno F, Morgan JD, Wu JY, Chen HY, Kim S, Chan W, Birzin ET, Yang YT, Pai LY, Zhang Z, Hayes EC, DaSilva CA, Tang W, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of benzoxathiin SERAMs with heteroatom-substituted amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
|
Inhibition of estrogen-mediated human breast adenocarcinoma (MCF-7) cell proliferation
|
Homo sapiens
|
1.4
nM
|
|
Journal : J. Med. Chem.
Title : Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands.
Year : 2005
Volume : 48
Issue : 2
First Page : 364
Last Page : 379
Authors : Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P.
Abstract : We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
|
In vitro inhibition of estradiol-stimulated MCF-7 breast cancer cell proliferation
|
Homo sapiens
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 9: Dihydrobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers.
Year : 2005
Volume : 15
Issue : 1
First Page : 107
Last Page : 113
Authors : Blizzard TA, Dininno F, Morgan JD, Chen HY, Wu JY, Kim S, Chan W, Birzin ET, Yang YT, Pai LY, Fitzgerald PM, Sharma N, Li Y, Zhang Z, Hayes EC, Dasilva CA, Tang W, Rohrer SP, Schaeffer JM, Hammond ML.
Abstract : A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
|
Antagonistic activity against estrogen receptor beta in presence of 0.1 nM estradiol
|
Homo sapiens
|
4.5
nM
|
|
Journal : J. Med. Chem.
Title : Differential response of estrogen receptor subtypes to 1,3-diarylindene and 2,3-diarylindene ligands.
Year : 2005
Volume : 48
Issue : 19
First Page : 5989
Last Page : 6003
Authors : Clegg NJ, Paruthiyil S, Leitman DC, Scanlan TS.
Abstract : Estrogen receptors (ERs) control transcription of genes important for normal human development and reproduction. The signaling networks are complex, and there is a need for a molecular level understanding of the roles of receptor subtypes ERalpha and ERbeta in normal physiology and as therapeutic targets. We synthesized two series of ER ligands, based on a common indene scaffold, in an attempt to develop compounds that can selectively modulate ER-mediated transcription. The 3-ethyl-1,2-diarylindenes, utilizing an amide linker for the 1-aryl extension, bind weakly to the ERs. The 2,3-diarylindenes bind with high affinity to the ER subtypes and demonstrate a range of different biological activities, both in transcriptional reporter gene assays and inhibition of estradiol-stimulated proliferation of MCF-7 cells. Several ligands differentiate between ERalpha and ERbeta subtypes at an estrogen response element (ERE), displaying various levels of partial to full agonist activity at ERalpha, while antagonizing estradiol action at ERbeta.
|
Antagonistic activity against estrogen receptor alpha in presence of 0.1 nM estradiol
|
Homo sapiens
|
0.03
nM
|
|
Journal : J. Med. Chem.
Title : Differential response of estrogen receptor subtypes to 1,3-diarylindene and 2,3-diarylindene ligands.
Year : 2005
Volume : 48
Issue : 19
First Page : 5989
Last Page : 6003
Authors : Clegg NJ, Paruthiyil S, Leitman DC, Scanlan TS.
Abstract : Estrogen receptors (ERs) control transcription of genes important for normal human development and reproduction. The signaling networks are complex, and there is a need for a molecular level understanding of the roles of receptor subtypes ERalpha and ERbeta in normal physiology and as therapeutic targets. We synthesized two series of ER ligands, based on a common indene scaffold, in an attempt to develop compounds that can selectively modulate ER-mediated transcription. The 3-ethyl-1,2-diarylindenes, utilizing an amide linker for the 1-aryl extension, bind weakly to the ERs. The 2,3-diarylindenes bind with high affinity to the ER subtypes and demonstrate a range of different biological activities, both in transcriptional reporter gene assays and inhibition of estradiol-stimulated proliferation of MCF-7 cells. Several ligands differentiate between ERalpha and ERbeta subtypes at an estrogen response element (ERE), displaying various levels of partial to full agonist activity at ERalpha, while antagonizing estradiol action at ERbeta.
|
Inhibition of binding to recombinant human ERalpha by scintillation proximity assay
|
Homo sapiens
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 14: application of novel antagonist side chains to existing platforms.
Year : 2005
Volume : 15
Issue : 23
First Page : 5124
Last Page : 5128
Authors : Blizzard TA, Morgan JD, Chan W, Birzin ET, Pai LY, Hayes EC, DaSilva CA, Mosley RT, Yang YT, Rohrer SP, Dininno F, Hammond ML.
Abstract : Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.
|
Inhibition of binding to recombinant human ERbeta by scintillation proximity assay
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 14: application of novel antagonist side chains to existing platforms.
Year : 2005
Volume : 15
Issue : 23
First Page : 5124
Last Page : 5128
Authors : Blizzard TA, Morgan JD, Chan W, Birzin ET, Pai LY, Hayes EC, DaSilva CA, Mosley RT, Yang YT, Rohrer SP, Dininno F, Hammond ML.
Abstract : Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.
|
Antiproliferative activity against human breast cancer MCF7 cell line in presence of 0.003 nM estradiol
|
Homo sapiens
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Estrogen receptor ligands. Part 14: application of novel antagonist side chains to existing platforms.
Year : 2005
Volume : 15
Issue : 23
First Page : 5124
Last Page : 5128
Authors : Blizzard TA, Morgan JD, Chan W, Birzin ET, Pai LY, Hayes EC, DaSilva CA, Mosley RT, Yang YT, Rohrer SP, Dininno F, Hammond ML.
Abstract : Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.
|
Binding affinity to ERalpha
|
Homo sapiens
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Novel chromene-derived selective estrogen receptor modulators useful for alleviating hot flushes and vaginal dryness.
Year : 2006
Volume : 49
Issue : 11
First Page : 3056
Last Page : 3059
Authors : Jain N, Kanojia RM, Xu J, Jian-Zhong G, Pacia E, Lai MT, Du F, Musto A, Allan G, Hahn D, Lundeen S, Sui Z.
Abstract : A novel SERM (selective estrogen receptor modulators), 1-(R), a chromene-derived bisbenzopyran, was discovered to alleviate hot flushes and effectively increase vaginal fluidity in rats. Moreover, 1-(R) was found to have beneficial effects on plasma cholesterol and bone metabolism while maintaining antiestrogenic activity in the uterus. The biological profile of its enantiomer 1-(S) was also evaluated.
|
Binding affinity to ERbeta
|
Homo sapiens
|
8.2
nM
|
|
Journal : J. Med. Chem.
Title : Novel chromene-derived selective estrogen receptor modulators useful for alleviating hot flushes and vaginal dryness.
Year : 2006
Volume : 49
Issue : 11
First Page : 3056
Last Page : 3059
Authors : Jain N, Kanojia RM, Xu J, Jian-Zhong G, Pacia E, Lai MT, Du F, Musto A, Allan G, Hahn D, Lundeen S, Sui Z.
Abstract : A novel SERM (selective estrogen receptor modulators), 1-(R), a chromene-derived bisbenzopyran, was discovered to alleviate hot flushes and effectively increase vaginal fluidity in rats. Moreover, 1-(R) was found to have beneficial effects on plasma cholesterol and bone metabolism while maintaining antiestrogenic activity in the uterus. The biological profile of its enantiomer 1-(S) was also evaluated.
|
Inhibition of estrogen receptor in Ishikawa cells
|
Homo sapiens
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel chromene-derived selective estrogen receptor modulators useful for alleviating hot flushes and vaginal dryness.
Year : 2006
Volume : 49
Issue : 11
First Page : 3056
Last Page : 3059
Authors : Jain N, Kanojia RM, Xu J, Jian-Zhong G, Pacia E, Lai MT, Du F, Musto A, Allan G, Hahn D, Lundeen S, Sui Z.
Abstract : A novel SERM (selective estrogen receptor modulators), 1-(R), a chromene-derived bisbenzopyran, was discovered to alleviate hot flushes and effectively increase vaginal fluidity in rats. Moreover, 1-(R) was found to have beneficial effects on plasma cholesterol and bone metabolism while maintaining antiestrogenic activity in the uterus. The biological profile of its enantiomer 1-(S) was also evaluated.
|
Inhibition of estrogen receptor in MCF7 cells
|
Homo sapiens
|
222.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel chromene-derived selective estrogen receptor modulators useful for alleviating hot flushes and vaginal dryness.
Year : 2006
Volume : 49
Issue : 11
First Page : 3056
Last Page : 3059
Authors : Jain N, Kanojia RM, Xu J, Jian-Zhong G, Pacia E, Lai MT, Du F, Musto A, Allan G, Hahn D, Lundeen S, Sui Z.
Abstract : A novel SERM (selective estrogen receptor modulators), 1-(R), a chromene-derived bisbenzopyran, was discovered to alleviate hot flushes and effectively increase vaginal fluidity in rats. Moreover, 1-(R) was found to have beneficial effects on plasma cholesterol and bone metabolism while maintaining antiestrogenic activity in the uterus. The biological profile of its enantiomer 1-(S) was also evaluated.
|
Displacement of [3H]estradiol from human recombinant ERalpha
|
Homo sapiens
|
20.6
nM
|
|
Journal : J. Med. Chem.
Title : Benzothiophene selective estrogen receptor modulators with modulated oxidative activity and receptor affinity.
Year : 2007
Volume : 50
Issue : 11
First Page : 2682
Last Page : 2692
Authors : Qin Z, Kastrati I, Chandrasena RE, Liu H, Yao P, Petukhov PA, Bolton JL, Thatcher GR.
Abstract : The regulation of estrogenic and antiestrogenic effects of selective estrogen receptor modulators (SERMs) is thought to underlie their clinical use. Most SERMs are polyaromatic phenols susceptible to oxidative metabolism to quinoids, which are proposed to be genotoxic. Conversely, the redox reactivity of SERMs may contribute to antioxidant and chemopreventive mechanisms, providing a new approach to improve the therapeutic properties of SERMs. An improved synthetic strategy was developed to generate a family of benzothiophene SERMs. Using computational modeling methods and measurements of antioxidant activity and estrogen receptor (ER) ligand binding, this SERM family was shown to provide both a range of ERalpha/ERbeta selectivity from 1.2- to 67-fold and a range of redox activity. Antioxidant activity was successfully modulated by varying a substituent remote from the OH group; the source of the antioxidant capacity. An efficient synthetic procedure is reported yielding benzothiophene SERMs wherein redox activity and ER affinity are modulated.
|
Displacement of [3H]estradiol from human recombinant ERbeta
|
Homo sapiens
|
557.0
nM
|
|
Journal : J. Med. Chem.
Title : Benzothiophene selective estrogen receptor modulators with modulated oxidative activity and receptor affinity.
Year : 2007
Volume : 50
Issue : 11
First Page : 2682
Last Page : 2692
Authors : Qin Z, Kastrati I, Chandrasena RE, Liu H, Yao P, Petukhov PA, Bolton JL, Thatcher GR.
Abstract : The regulation of estrogenic and antiestrogenic effects of selective estrogen receptor modulators (SERMs) is thought to underlie their clinical use. Most SERMs are polyaromatic phenols susceptible to oxidative metabolism to quinoids, which are proposed to be genotoxic. Conversely, the redox reactivity of SERMs may contribute to antioxidant and chemopreventive mechanisms, providing a new approach to improve the therapeutic properties of SERMs. An improved synthetic strategy was developed to generate a family of benzothiophene SERMs. Using computational modeling methods and measurements of antioxidant activity and estrogen receptor (ER) ligand binding, this SERM family was shown to provide both a range of ERalpha/ERbeta selectivity from 1.2- to 67-fold and a range of redox activity. Antioxidant activity was successfully modulated by varying a substituent remote from the OH group; the source of the antioxidant capacity. An efficient synthetic procedure is reported yielding benzothiophene SERMs wherein redox activity and ER affinity are modulated.
|
Antagonist activity at human ERalpha expressed in african green monkey CV1 cells assessed as inhibition of estrogen like activity after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
0.46
nM
|
|
Journal : J. Nat. Prod.
Title : Bioactive compounds from Peperomia pellucida.
Year : 2006
Volume : 69
Issue : 2
First Page : 247
Last Page : 250
Authors : Xu S, Li N, Ning MM, Zhou CH, Yang QR, Wang MW.
Abstract : Five new compounds (1-5), including two secolignans, two tetrahydrofuran lignans, and one highly methoxylated dihydronaphthalenone, were isolated from the whole plant of Peperomia pellucida. These compounds were accompanied by the known peperomins A, B, C, and E, 7,8-trans-8,8'-trans-7',8'-cis-7,7'-bis(5-methoxy-3,4-methylenedioxyphenyl)-8-acetoxymethyl-8'-hydroxymethyltetrahydrofuran, 7,8-trans-8,8'-trans-7',8'-cis-7-(5-methoxy-3,4-methylenedioxyphenyl)-7'-(4-hydroxy-3,5-dimethoxyphenyl)-8,8'-diacetoxymethyltetrahydrofuran, sesamin, and isoswertisin. New structures were elucidated mainly by NMR and MS techniques, and anticancer activities evaluated in HL-60, MCF-7, and HeLa cell lines. Compound 1 and peperomin E show growth inhibitory effects on the three cancer cell lines with IC(50) values ranging between 1.4 and 9.1 and between 1.8 and 11.1 microM, respectively. Compound 2 has a weak suppressive activity on HL-60 cells (IC(50) = 10.8 microM), while 7,8-trans-8,8'-trans-7',8'-cis-7,7'-bis(5-methoxy-3,4-methylenedioxyphenyl)-8-acetoxymethyl-8'-hydroxymethyltetrahydrofuran exhibits estrogen-like properties (EC(50) = 3.1 microM) in CV-1 cells transfected with human estrogen receptor (ERalpha).
|
Displacement of [3H]estradiol from full length biotinylated human ERalpha by scintillation proximity assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands.
Year : 2008
Volume : 18
Issue : 18
First Page : 5075
Last Page : 5077
Authors : Fang J, Akwabi-Ameyaw A, Britton JE, Katamreddy SR, Navas F, Miller AB, Williams SP, Gray DW, Orband-Miller LA, Shearin J, Heyer D.
Abstract : A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ERalpha and ERbeta binding affinity ranging from micromolar to low nanomolar.
|
Displacement of [3H]estradiol from full length biotinylated human ERbeta by scintillation proximity assay
|
Homo sapiens
|
23.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands.
Year : 2008
Volume : 18
Issue : 18
First Page : 5075
Last Page : 5077
Authors : Fang J, Akwabi-Ameyaw A, Britton JE, Katamreddy SR, Navas F, Miller AB, Williams SP, Gray DW, Orband-Miller LA, Shearin J, Heyer D.
Abstract : A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ERalpha and ERbeta binding affinity ranging from micromolar to low nanomolar.
|
Activity against estrogen receptor alpha
|
None
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Recent developments in fragment-based drug discovery.
Year : 2008
Volume : 51
Issue : 13
First Page : 3661
Last Page : 3680
Authors : Congreve M, Chessari G, Tisi D, Woodhead AJ.
|
Inhibition of fluormone ES2 binding to estrogen receptor beta after 1 hr by fluorescence polarization assay
|
None
|
8.2
nM
|
|
Journal : J. Med. Chem.
Title : Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms.
Year : 2009
Volume : 52
Issue : 23
First Page : 7544
Last Page : 7569
Authors : Jain N, Xu J, Kanojia RM, Du F, Jian-Zhong G, Pacia E, Lai MT, Musto A, Allan G, Reuman M, Li X, Hahn D, Cousineau M, Peng S, Ritchie D, Russell R, Lundeen S, Sui Z.
Abstract : As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
|
Displacement of radiolabeled estrogen from estrogen receptor alpha by scintillation counting
|
None
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms.
Year : 2009
Volume : 52
Issue : 23
First Page : 7544
Last Page : 7569
Authors : Jain N, Xu J, Kanojia RM, Du F, Jian-Zhong G, Pacia E, Lai MT, Musto A, Allan G, Reuman M, Li X, Hahn D, Cousineau M, Peng S, Ritchie D, Russell R, Lundeen S, Sui Z.
Abstract : As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
|
Antagonist activity at estrogen receptor in human Ishikawa cells assessed as 17-beta-estradiol-induced alkaline phosphatase activity after 3 days by chemiluminescence assay
|
Homo sapiens
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms.
Year : 2009
Volume : 52
Issue : 23
First Page : 7544
Last Page : 7569
Authors : Jain N, Xu J, Kanojia RM, Du F, Jian-Zhong G, Pacia E, Lai MT, Musto A, Allan G, Reuman M, Li X, Hahn D, Cousineau M, Peng S, Ritchie D, Russell R, Lundeen S, Sui Z.
Abstract : As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
|
Antagonist activity at estrogen receptor in human MCF7 cells assessed as 17-beta-estradiol-induced cell proliferation after 24 hrs by [14C]thymidine incorporation assay
|
Homo sapiens
|
222.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms.
Year : 2009
Volume : 52
Issue : 23
First Page : 7544
Last Page : 7569
Authors : Jain N, Xu J, Kanojia RM, Du F, Jian-Zhong G, Pacia E, Lai MT, Musto A, Allan G, Reuman M, Li X, Hahn D, Cousineau M, Peng S, Ritchie D, Russell R, Lundeen S, Sui Z.
Abstract : As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
|
Uterotropic activity in rat assessed as inhibition of estrone-stimulated uterine weight at 1 mg/kg, po QD after 3 days
|
Rattus norvegicus
|
105.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms.
Year : 2009
Volume : 52
Issue : 23
First Page : 7544
Last Page : 7569
Authors : Jain N, Xu J, Kanojia RM, Du F, Jian-Zhong G, Pacia E, Lai MT, Musto A, Allan G, Reuman M, Li X, Hahn D, Cousineau M, Peng S, Ritchie D, Russell R, Lundeen S, Sui Z.
Abstract : As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
|
Antagonist activity at human ERalpha E353A mutant expressed in HEK293T cells co-expressing ERE assessed as inhibition of ES8-induced transactivation by luciferase reporter gene assay
|
Homo sapiens
|
56.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A mutant selective anti-estrogen is a pure antagonist on EREs and AP-1 response elements.
Year : 2010
Volume : 20
Issue : 17
First Page : 5258
Last Page : 5261
Authors : Jain D, Koh JT.
Abstract : Estrogen receptors (ERs) regulate gene transcription through classic estrogen response elements (EREs) as well as AP-1 responsive genes. The common SERMs Raloxifene, Tamoxifen, and ICI164384 function as ER antagonists on EREs but as ERbeta agonists/partial agonists on AP-1 responsive genes. While developing a mutant selective analog of Raloxifene, that is an antagonist of ERalpha(E353A), we discovered an antagonist of wild-type ERalpha and ERbeta that is also an antagonist of ERbeta/AP-1 response. The analog, DRL527, represses basal AP-1 gene expression and antagonizes Raloxifene stimulated AP-1 expression. Therefore DRL527 has a unique, previously unreported, ERE/AP-1 activity profile.
|
Antagonist activity at human wild type ERbeta expressed in HEK293T cells co-expressing ERE assessed as inhibition of estradiol-induced transactivation by luciferase reporter gene assay
|
Homo sapiens
|
6.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A mutant selective anti-estrogen is a pure antagonist on EREs and AP-1 response elements.
Year : 2010
Volume : 20
Issue : 17
First Page : 5258
Last Page : 5261
Authors : Jain D, Koh JT.
Abstract : Estrogen receptors (ERs) regulate gene transcription through classic estrogen response elements (EREs) as well as AP-1 responsive genes. The common SERMs Raloxifene, Tamoxifen, and ICI164384 function as ER antagonists on EREs but as ERbeta agonists/partial agonists on AP-1 responsive genes. While developing a mutant selective analog of Raloxifene, that is an antagonist of ERalpha(E353A), we discovered an antagonist of wild-type ERalpha and ERbeta that is also an antagonist of ERbeta/AP-1 response. The analog, DRL527, represses basal AP-1 gene expression and antagonizes Raloxifene stimulated AP-1 expression. Therefore DRL527 has a unique, previously unreported, ERE/AP-1 activity profile.
|
Antagonist activity at human wild type ERalpha expressed in HEK293T cells co-expressing ERE assessed as inhibition of estradiol-induced transactivation by luciferase reporter gene assay
|
Homo sapiens
|
0.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A mutant selective anti-estrogen is a pure antagonist on EREs and AP-1 response elements.
Year : 2010
Volume : 20
Issue : 17
First Page : 5258
Last Page : 5261
Authors : Jain D, Koh JT.
Abstract : Estrogen receptors (ERs) regulate gene transcription through classic estrogen response elements (EREs) as well as AP-1 responsive genes. The common SERMs Raloxifene, Tamoxifen, and ICI164384 function as ER antagonists on EREs but as ERbeta agonists/partial agonists on AP-1 responsive genes. While developing a mutant selective analog of Raloxifene, that is an antagonist of ERalpha(E353A), we discovered an antagonist of wild-type ERalpha and ERbeta that is also an antagonist of ERbeta/AP-1 response. The analog, DRL527, represses basal AP-1 gene expression and antagonizes Raloxifene stimulated AP-1 expression. Therefore DRL527 has a unique, previously unreported, ERE/AP-1 activity profile.
|
Antagonist activity at human ERbeta E305A mutant expressed in HEK293T cells co-expressing ERE assessed as inhibition of ES8-induced transactivation by luciferase reporter gene assay
|
Homo sapiens
|
577.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A mutant selective anti-estrogen is a pure antagonist on EREs and AP-1 response elements.
Year : 2010
Volume : 20
Issue : 17
First Page : 5258
Last Page : 5261
Authors : Jain D, Koh JT.
Abstract : Estrogen receptors (ERs) regulate gene transcription through classic estrogen response elements (EREs) as well as AP-1 responsive genes. The common SERMs Raloxifene, Tamoxifen, and ICI164384 function as ER antagonists on EREs but as ERbeta agonists/partial agonists on AP-1 responsive genes. While developing a mutant selective analog of Raloxifene, that is an antagonist of ERalpha(E353A), we discovered an antagonist of wild-type ERalpha and ERbeta that is also an antagonist of ERbeta/AP-1 response. The analog, DRL527, represses basal AP-1 gene expression and antagonizes Raloxifene stimulated AP-1 expression. Therefore DRL527 has a unique, previously unreported, ERE/AP-1 activity profile.
|
Displacement of [3H]LSD from human cloned 5HT2B receptor expressed in CHO cells by liquid scintillation counting
|
Homo sapiens
|
69.0
nM
|
|
Journal : J. Med. Chem.
Title : Development, validation, and use of quantitative structure-activity relationship models of 5-hydroxytryptamine (2B) receptor ligands to identify novel receptor binders and putative valvulopathic compounds among common drugs.
Year : 2010
Volume : 53
Issue : 21
First Page : 7573
Last Page : 7586
Authors : Hajjo R, Grulke CM, Golbraikh A, Setola V, Huang XP, Roth BL, Tropsha A.
Abstract : Some antipsychotic drugs are known to cause valvular heart disease by activating serotonin 5-HT(2B) receptors. We have developed and validated binary classification QSAR models capable of predicting potential 5-HT(2B) actives. The classification accuracies of the models built to discriminate 5-HT(2B) actives from the inactives were as high as 80% for the external test set. These models were used to screen in silico 59,000 compounds included in the World Drug Index, and 122 compounds were predicted as actives with high confidence. Ten of them were tested in radioligand binding assays and nine were found active, suggesting a success rate of 90%. All validated actives were then tested in functional assays, and one compound was identified as a true 5-HT(2B) agonist. We suggest that the QSAR models developed in this study could be used as reliable predictors to flag drug candidates that are likely to cause valvulopathy.
|
Inhibition of human aldehyde oxidase
|
Homo sapiens
|
3.0
nM
|
|
Inhibition of human aldehyde oxidase
|
Homo sapiens
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Aldehyde oxidase: an enzyme of emerging importance in drug discovery.
Year : 2010
Volume : 53
Issue : 24
First Page : 8441
Last Page : 8460
Authors : Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran TD.
|
Inhibition of mouse aldehyde oxidase
|
Mus musculus
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Aldehyde oxidase: an enzyme of emerging importance in drug discovery.
Year : 2010
Volume : 53
Issue : 24
First Page : 8441
Last Page : 8460
Authors : Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran TD.
|
Inhibition of monkey aldehyde oxidase
|
Macaca fascicularis
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Aldehyde oxidase: an enzyme of emerging importance in drug discovery.
Year : 2010
Volume : 53
Issue : 24
First Page : 8441
Last Page : 8460
Authors : Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran TD.
|
Antiosteoporotic activity in Sprague-Dawley rat [45Ca] pre-labeled bone assessed as inhibition of PTH-induced bone resorption after 21 days relative to control
|
Rattus norvegicus
|
38.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of 1,3-biarylsulfanyl derivatives as new anti-breast cancer agents.
Year : 2011
Volume : 19
Issue : 18
First Page : 5409
Last Page : 5419
Authors : Kumar A, Tripathi VD, Kumar P, Gupta LP, Akanksha, Trivedi R, Bid H, Nayak VL, Siddiqui JA, Chakravarti B, Saxena R, Dwivedi A, Siddiquee MI, Siddiqui U, Konwar R, Chattopadhyay N.
Abstract : A new series of 1,3-biarylsulfanyl derivatives (homodibenzyl core motif) have been designed and synthesized as new estrogen receptor ligands by chopping benzothiophene core of raloxifene to engender seco-raloxifene scaffold. All the synthesized compounds were screened for anti-proliferative, anti-osteoporotic, and anti-implantation activity. Compounds (35, 36) having basic amino anti-estrogenic side chain were exhibiting potential anti-proliferative activity in MCF-7, MDA-MB-231 and ishikawa cell lines. Some of the synthesized compounds having homodibenzyl motif (5, 8, 10) have shown moderate anti-osteoporotic activity.
|
DRUGMATRIX: Opiate kappa (OP2, KOP) radioligand binding (ligand: [3H] Diprenorphine)
|
None
|
641.0
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: Opiate mu (OP3, MOP) radioligand binding (ligand: [3H] Diprenorphine)
|
None
|
477.0
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: Serotonin (5-Hydroxytryptamine) 5-HT1B radioligand binding (ligand: [125I] Cyanopindolol)
|
Rattus norvegicus
|
846.0
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: Serotonin (5-Hydroxytryptamine) 5-HT2A radioligand binding (ligand: [3H] Ketanserin)
|
None
|
414.0
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: Acetylcholinesterase enzyme inhibition (substrate: acetylthiocholine)
|
None
|
400.0
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: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
892.0
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: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
973.0
nM
|
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
478.0
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: Alpha-2A adrenergic receptor radioligand binding (ligand: MK-912)
|
None
|
624.0
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: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
738.0
nM
|
|
DRUGMATRIX: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
107.0
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: Norepinephrine Transporter radioligand binding (ligand: [125I] RTI-55)
|
None
|
282.0
nM
|
|
DRUGMATRIX: Norepinephrine Transporter radioligand binding (ligand: [125I] RTI-55)
|
None
|
280.0
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: Calcium Channel Type L, Benzothiazepine radioligand binding (ligand: [3H] Diltiazem)
|
Rattus norvegicus
|
414.0
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Benzothiazepine radioligand binding (ligand: [3H] Diltiazem)
|
Rattus norvegicus
|
368.0
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: Calcium Channel Type L, Dihydropyridine radioligand binding (ligand: [3H] Nitrendipine)
|
Rattus norvegicus
|
388.0
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Dihydropyridine radioligand binding (ligand: [3H] Nitrendipine)
|
Rattus norvegicus
|
249.0
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: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
355.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
226.0
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: Serotonin (5-Hydroxytryptamine) 5-HT2C radioligand binding (ligand: [3H] Mesulergine)
|
None
|
617.0
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: Sigma1 radioligand binding (ligand: [3H] Haloperidol)
|
None
|
681.0
nM
|
|
DRUGMATRIX: Sigma1 radioligand binding (ligand: [3H] Haloperidol)
|
None
|
286.0
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: Sigma2 radioligand binding (ligand: [3H] Ifenprodil)
|
Rattus norvegicus
|
385.0
nM
|
|
DRUGMATRIX: Sigma2 radioligand binding (ligand: [3H] Ifenprodil)
|
Rattus norvegicus
|
237.0
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: Sodium Channel, Site 2 radioligand binding (ligand: [3H] Batrachotoxin)
|
Rattus norvegicus
|
527.0
nM
|
|
DRUGMATRIX: Sodium Channel, Site 2 radioligand binding (ligand: [3H] Batrachotoxin)
|
Rattus norvegicus
|
480.0
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: Calcium Channel Type L, Phenylalkylamine radioligand binding (ligand: [3H] (-)-Desmethoxyverapamil (D-888))
|
Rattus norvegicus
|
148.0
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Phenylalkylamine radioligand binding (ligand: [3H] (-)-Desmethoxyverapamil (D-888))
|
Rattus norvegicus
|
144.0
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: Dopamine D2L radioligand binding (ligand: [3H] Spiperone)
|
None
|
391.0
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: Dopamine D3 radioligand binding (ligand: [3H] Spiperone)
|
None
|
531.0
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: Estrogen ERalpha radioligand binding (ligand: [3H] Estradiol)
|
None
|
0.553
nM
|
|
DRUGMATRIX: Estrogen ERalpha radioligand binding (ligand: [3H] Estradiol)
|
None
|
0.158
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
|
Antiproliferative activity against human MCF7 cells
|
Homo sapiens
|
0.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Recent advances in the synthesis of raloxifene: a selective estrogen receptor modulator.
Year : 2012
Volume : 51
First Page : 17
Last Page : 34
Authors : Dadiboyena S.
Abstract : Estrogens are a group of steroids that exert important effects on reproductive and many non-reproductive tissues. Selective estrogen receptor modulators (SERM) are a class of therapeutic agents widely prescribed for the treatment and prevention of breast cancer, osteoporosis, and postmenopausal symptoms. Raloxifene, an example of oral SERM is prescribed primarily for the treatment and prevention of postmenopausal disorders in woman. The current review provides an outline of practical methodologies used to access benzothiophenyl scaffolds of raloxifene and relevant structural analogs. The contents are discussed in five sections: (a) synthesis of raloxifene, (b) organometallic analogs, (c) radiolabelled analogs, (d) constrained raloxifene analogs, and (e) other oxygen, sulfur, and nitrogen based raloxifene analogs. In addition to the synthesis, biological activity of a few synthetic analogs has been discussed.
|
Displacement of [3H]estradiol from ERalpha after 4 hrs by scintillation counting
|
None
|
0.37
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Hydrophobic Interactions Improve Selectivity to ERα for Ben-zothiophene SERMs.
Year : 2012
Volume : 3
Issue : 3
First Page : 207
Last Page : 210
Authors : Chalmers MJ, Wang Y, Novick S, Sato M, Bryant HU, Montrose-Rafizdeh C, Griffin PR, Dodge JA.
Abstract : The discovery, pharmacology, and biophysical characterization of an ERα selective benzothiophene (BTPα) is described. BTPα (4) is a high affinity ligand with 140-fold greater selectivity for ERα (K(i)=0.25 nM) over ERbeta (K(i)=35 nM). In rodent models of estrogen action, BTPα blocks the effects of estrogen in the uterus but mimics the effects estrogen on bone. The basis of ERα selectivity for BTPα was evaluated by using protein crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry. HDX data supports that the n-butyl chain of BTPα stabilizes helix 7 in ERα relative to that of ERβ which we propose leads to an enhancement of affinity to the alpha receptor sub-type.
|
Displacement of [3H]estradiol from ERbeta after 4 hrs by scintillation counting
|
None
|
2.74
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Hydrophobic Interactions Improve Selectivity to ERα for Ben-zothiophene SERMs.
Year : 2012
Volume : 3
Issue : 3
First Page : 207
Last Page : 210
Authors : Chalmers MJ, Wang Y, Novick S, Sato M, Bryant HU, Montrose-Rafizdeh C, Griffin PR, Dodge JA.
Abstract : The discovery, pharmacology, and biophysical characterization of an ERα selective benzothiophene (BTPα) is described. BTPα (4) is a high affinity ligand with 140-fold greater selectivity for ERα (K(i)=0.25 nM) over ERbeta (K(i)=35 nM). In rodent models of estrogen action, BTPα blocks the effects of estrogen in the uterus but mimics the effects estrogen on bone. The basis of ERα selectivity for BTPα was evaluated by using protein crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry. HDX data supports that the n-butyl chain of BTPα stabilizes helix 7 in ERα relative to that of ERβ which we propose leads to an enhancement of affinity to the alpha receptor sub-type.
|
Binding affinity to ERalpha ligand binding domain
|
None
|
0.38
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Hydrophobic Interactions Improve Selectivity to ERα for Ben-zothiophene SERMs.
Year : 2012
Volume : 3
Issue : 3
First Page : 207
Last Page : 210
Authors : Chalmers MJ, Wang Y, Novick S, Sato M, Bryant HU, Montrose-Rafizdeh C, Griffin PR, Dodge JA.
Abstract : The discovery, pharmacology, and biophysical characterization of an ERα selective benzothiophene (BTPα) is described. BTPα (4) is a high affinity ligand with 140-fold greater selectivity for ERα (K(i)=0.25 nM) over ERbeta (K(i)=35 nM). In rodent models of estrogen action, BTPα blocks the effects of estrogen in the uterus but mimics the effects estrogen on bone. The basis of ERα selectivity for BTPα was evaluated by using protein crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry. HDX data supports that the n-butyl chain of BTPα stabilizes helix 7 in ERα relative to that of ERβ which we propose leads to an enhancement of affinity to the alpha receptor sub-type.
|
Displacement of [3H]LSD from human 5HT6 receptor expressed in HEK293 cells after 1.5 hrs by liquid scintillation counting
|
Homo sapiens
|
750.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemocentric informatics approach to drug discovery: identification and experimental validation of selective estrogen receptor modulators as ligands of 5-hydroxytryptamine-6 receptors and as potential cognition enhancers.
Year : 2012
Volume : 55
Issue : 12
First Page : 5704
Last Page : 5719
Authors : Hajjo R, Setola V, Roth BL, Tropsha A.
Abstract : We have devised a chemocentric informatics methodology for drug discovery integrating independent approaches to mining biomolecular databases. As a proof of concept, we have searched for novel putative cognition enhancers. First, we generated Quantitative Structure-Activity Relationship (QSAR) models of compounds binding to 5-hydroxytryptamine-6 receptor (5-HT(6)R), a known target for cognition enhancers, and employed these models for virtual screening to identify putative 5-HT(6)R actives. Second, we queried chemogenomics data from the Connectivity Map ( http://www.broad.mit.edu/cmap/ ) with the gene expression profile signatures of Alzheimer's disease patients to identify compounds putatively linked to the disease. Thirteen common hits were tested in 5-HT(6)R radioligand binding assays and ten were confirmed as actives. Four of them were known selective estrogen receptor modulators that were never reported as 5-HT(6)R ligands. Furthermore, nine of the confirmed actives were reported elsewhere to have memory-enhancing effects. The approaches discussed herein can be used broadly to identify novel drug-target-disease associations.
|
Inhibition of Homo sapiens (human) aldehyde oxidase
|
Homo sapiens
|
8.0
nM
|
|
Journal : J Agric Food Chem
Title : Neonicotinoid insecticides: oxidative stress in planta and metallo-oxidase inhibition.
Year : 2011
Volume : 59
Issue : 9
First Page : 4860
Last Page : 4867
Authors : Ford KA, Gulevich AG, Swenson TL, Casida JE.
Abstract : Neonicotinoids not only control insect pests but also sometimes independently alter plant growth and response to stress. We find that imidacloprid, thiacloprid, acetamiprid, thiamethoxam, and clothianidin but not nitenpyram and dinotefuran induce foliar lesions and peroxidative damage in soybean ( Glycine max ) seedlings assayed with the 3,3'-diaminobenzidine stain. The chloropyridinyl-carboxylic acid (COOH) but not the -carboxaldehyde (CHO) metabolites induce peroxidative damage but in a different pattern. Surprisingly, the chlorothiazolyl -CHO and -COOH metabolites induce chlorosis but no clear superimposable peroxidative damage or cell death. Four metallo-oxidases known to modulate reactive oxygen species were not sensitive in vitro to the parent neonicotinoid itself but were to several CHO and COOH metabolites and related compounds, with a sensitivity order of CHO > COOH and tyrosinase > xanthine oxidase and aldehyde oxidase > catalase. Although metallo-oxidase inhibition does not correlate overall with lesion formation, it may play an as yet unknown role in plant response to neonicotinoids.
|
Estrogen antagonistic activity in immature Rattus norvegicus Sprague-Dawley (rat) assessed as inhibition of ethynylestradiol-induced increase in uterine weight at 10 mg/kg, po qd for 3 days
|
Rattus norvegicus
|
57.0
%
|
|
Journal : Med Chem Res
Title : In vivo evaluation of substituted 3-phenyl,7-methoxy-benzopyrans as modified estrogens
Year : 2010
Volume : 19
Issue : 1
First Page : 25
Last Page : 32
Authors : Gupta A, Keshri G, Singh MM, Ray S
|
Antagonist activity at human GTS-tagged FXR at 15 uM after 20 mins by TR-FRET assay
|
Homo sapiens
|
71.4
%
|
|
Journal : Bioorg. Med. Chem.
Title : Development of time resolved fluorescence resonance energy transfer-based assay for FXR antagonist discovery.
Year : 2013
Volume : 21
Issue : 14
First Page : 4266
Last Page : 4278
Authors : Yu DD, Lin W, Chen T, Forman BM.
Abstract : FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism. FXR ligands have been investigated in preclinical studies for targeted therapy against metabolic diseases, but have shown limitations. Therefore, there is a need for new agonist or antagonist ligands of FXR, both for potential clinical applications, as well as to further elucidate its biological functions. Here we describe the use of the X-ray crystal structure of FXR complexed with the potent small molecule agonist GW4064 to design and synthesize a novel fluorescent, high-affinity probe (DY246) for time resolved fluorescence resonance energy transfer (TR-FRET) assays. We then used the TR-FRET assay for high throughput screening of a library of over 5000 bioactive compounds. From this library, we identified 13 compounds that act as putative FXR transcriptional antagonists.
|
Antagonist activity at human recombinant dopamine D2 long receptor expressed in CHOK1 cells coexpressing mitochondrial apoaequorin assessed as inhibition of agonist-induced effect at 50 uM after 15 mins by luminometric analysis relative to haloperidol
|
Homo sapiens
|
88.0
%
|
|
Journal : J. Med. Chem.
Title : Experimental confirmation of new drug-target interactions predicted by Drug Profile Matching.
Year : 2013
Volume : 56
Issue : 21
First Page : 8377
Last Page : 8388
Authors : Végner L, Peragovics Á, Tombor L, Jelinek B, Czobor P, Bender A, Simon Z, Málnási-Csizmadia A.
Abstract : We recently introduced Drug Profile Matching (DPM), a novel affinity fingerprinting-based in silico drug repositioning approach. DPM is able to quantitatively predict the complete effect profiles of compounds via probability scores. In the present work, in order to investigate the predictive power of DPM, three effect categories, namely, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor, and dopamine agent, were selected and predictions were verified by literature analysis as well as experimentally. A total of 72% of the newly predicted and tested dopaminergic compounds were confirmed by tests on D1 and D2 expressing cell cultures. 33% and 23% of the ACE and COX inhibitory predictions were confirmed by in vitro tests, respectively. Dose-dependent inhibition curves were measured for seven drugs, and their inhibitory constants (Ki) were determined. Our study overall demonstrates that DPM is an effective approach to reveal novel drug-target pairs that may result in repositioning these drugs.
|
Antagonist activity at human recombinant dopamine D1 receptor expressed in CHOK1 cells assessed as inhibition of agonist-induced cAMP accumulation at 100 uM preincubated for 10 mins prior to agonist addition measured after 30 mins by HTRF assay relative to SCH23390
|
Homo sapiens
|
97.0
%
|
|
Journal : J. Med. Chem.
Title : Experimental confirmation of new drug-target interactions predicted by Drug Profile Matching.
Year : 2013
Volume : 56
Issue : 21
First Page : 8377
Last Page : 8388
Authors : Végner L, Peragovics Á, Tombor L, Jelinek B, Czobor P, Bender A, Simon Z, Málnási-Csizmadia A.
Abstract : We recently introduced Drug Profile Matching (DPM), a novel affinity fingerprinting-based in silico drug repositioning approach. DPM is able to quantitatively predict the complete effect profiles of compounds via probability scores. In the present work, in order to investigate the predictive power of DPM, three effect categories, namely, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor, and dopamine agent, were selected and predictions were verified by literature analysis as well as experimentally. A total of 72% of the newly predicted and tested dopaminergic compounds were confirmed by tests on D1 and D2 expressing cell cultures. 33% and 23% of the ACE and COX inhibitory predictions were confirmed by in vitro tests, respectively. Dose-dependent inhibition curves were measured for seven drugs, and their inhibitory constants (Ki) were determined. Our study overall demonstrates that DPM is an effective approach to reveal novel drug-target pairs that may result in repositioning these drugs.
|
Inhibition of IDO1 (unknown origin) at highest soluble concentration using L-tryptophan substrate incubated for 60 mins by HPLC
|
Homo sapiens
|
0.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.
Year : 2014
Volume : 84
First Page : 284
Last Page : 301
Authors : Röhrig UF, Majjigapu SR, Chambon M, Bron S, Pilotte L, Colau D, Van den Eynde BJ, Turcatti G, Vogel P, Zoete V, Michielin O.
Abstract : Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 μM under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 inhibitor scaffold, the imidazole antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity.
|
Uncompetitive inhibition of human liver cytosolic aldehyde oxidase using phthalazine as substrate assessed as enzyme-substrate complex by Lineweaver-Burk plot analysis
|
Homo sapiens
|
0.87
nM
|
|
Journal : Drug Metab. Dispos.
Title : Evidence for substrate-dependent inhibition profiles for human liver aldehyde oxidase.
Year : 2013
Volume : 41
Issue : 1
First Page : 24
Last Page : 29
Authors : Barr JT, Jones JP.
Abstract : The goal of this study was to provide a reasonable assessment of how probe substrate selection may impact the results of in vitro aldehyde oxidase (AO) inhibition experiments. Here, we used a previously studied set of seven known AO inhibitors to probe the inhibition profile of a pharmacologically relevant substrate N-[(2-dimethylamino)ethyl]acridine-4-carboxamide (DACA). DACA oxidation in human liver cytosol was characterized with a measured V(max) of 2.3 ± 0.08 nmol product · min(-1) · mg(-1) and a K(m) of 6.3 ± 0.8 µM. The K(ii) and K(is) values describing the inhibition of DACA oxidation by the panel of seven inhibitors were tabulated and compared with previous findings with phthalazine as the substrate. In every case, the inhibition profile shifted to a much less uncompetitive mode of inhibition for DACA relative to phthalazine. With the exception of one inhibitor, raloxifene, this change in inhibition profile seems to be a result of a decrease in the uncompetitive mode of inhibition (an affected K(ii) value), whereas the competitive mode (K(is)) seems to be relatively consistent between substrates. Raloxifene was found to inhibit competitively when using DACA as a probe, and a previous report showed that raloxifene inhibited uncompetitively with other substrates. The relevance of these data to the mechanistic understanding of aldehyde oxidase inhibition and potential implications on drug-drug interactions is discussed. Overall, it appears that the choice in substrate may be critical when conducting mechanistic inhibition or in vitro drug-drug interactions prediction studies with AO.
|
Competitive inhibition of human liver cytosolic aldehyde oxidase using DACA as substrate assessed as free enzyme by Lineweaver-Burk plot analysis
|
Homo sapiens
|
2.3
nM
|
|
Journal : Drug Metab. Dispos.
Title : Evidence for substrate-dependent inhibition profiles for human liver aldehyde oxidase.
Year : 2013
Volume : 41
Issue : 1
First Page : 24
Last Page : 29
Authors : Barr JT, Jones JP.
Abstract : The goal of this study was to provide a reasonable assessment of how probe substrate selection may impact the results of in vitro aldehyde oxidase (AO) inhibition experiments. Here, we used a previously studied set of seven known AO inhibitors to probe the inhibition profile of a pharmacologically relevant substrate N-[(2-dimethylamino)ethyl]acridine-4-carboxamide (DACA). DACA oxidation in human liver cytosol was characterized with a measured V(max) of 2.3 ± 0.08 nmol product · min(-1) · mg(-1) and a K(m) of 6.3 ± 0.8 µM. The K(ii) and K(is) values describing the inhibition of DACA oxidation by the panel of seven inhibitors were tabulated and compared with previous findings with phthalazine as the substrate. In every case, the inhibition profile shifted to a much less uncompetitive mode of inhibition for DACA relative to phthalazine. With the exception of one inhibitor, raloxifene, this change in inhibition profile seems to be a result of a decrease in the uncompetitive mode of inhibition (an affected K(ii) value), whereas the competitive mode (K(is)) seems to be relatively consistent between substrates. Raloxifene was found to inhibit competitively when using DACA as a probe, and a previous report showed that raloxifene inhibited uncompetitively with other substrates. The relevance of these data to the mechanistic understanding of aldehyde oxidase inhibition and potential implications on drug-drug interactions is discussed. Overall, it appears that the choice in substrate may be critical when conducting mechanistic inhibition or in vitro drug-drug interactions prediction studies with AO.
|
Binding affinity to ERalpha (unknown origin)
|
Homo sapiens
|
0.43
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structural features underlying raloxifene's biophysical interaction with bone matrix.
Year : 2016
Volume : 24
Issue : 4
First Page : 759
Last Page : 767
Authors : Bivi N, Hu H, Chavali B, Chalmers MJ, Reutter CT, Durst GL, Riley A, Sato M, Allen MR, Burr DD, Dodge JA.
Abstract : Raloxifene, a selective estrogen receptor modulator (SERM), reduces fracture risk at least in part by improving the mechanical properties of bone in a cell- and estrogen receptor-independent manner. In this study, we determined that raloxifene directly interacts with the bone tissue. Through the use of multiple and complementary biophysical techniques including nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), we show that raloxifene interacts specifically with the organic component or the organic/mineral composite, and not with hydroxyapatite. Structure-activity studies reveal that the basic side chain of raloxifene is an instrumental determinant in the interaction with bone. Thus, truncation of portions of the side chain reduces bone binding and also diminishes the increase in mechanical properties. Our results support a model wherein the piperidine interacts with bone matrix through electrostatic interactions with the piperidine nitrogen and through hydrophobic interactions (van der Waals) with the aliphatic groups in the side chain and the benzothiophene core. Furthermore, in silico prediction of the potential binding sites on the surface of collagen revealed the presence of a groove with sufficient space to accommodate raloxifene analogs. The hydroxyl groups on the benzothiophene nucleus, which are necessary for binding of SERMs to the estrogen receptor, are not required for binding to the bone surface, but mediate a more robust binding of the compound to the bone powder. In conclusion, we report herein a novel property of raloxifene analogs that allows them to interact with the bone tissue through potential contacts with the organic matrix and in particular collagen.
|
Binding affinity to ERbeta (unknown origin)
|
Homo sapiens
|
4.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structural features underlying raloxifene's biophysical interaction with bone matrix.
Year : 2016
Volume : 24
Issue : 4
First Page : 759
Last Page : 767
Authors : Bivi N, Hu H, Chavali B, Chalmers MJ, Reutter CT, Durst GL, Riley A, Sato M, Allen MR, Burr DD, Dodge JA.
Abstract : Raloxifene, a selective estrogen receptor modulator (SERM), reduces fracture risk at least in part by improving the mechanical properties of bone in a cell- and estrogen receptor-independent manner. In this study, we determined that raloxifene directly interacts with the bone tissue. Through the use of multiple and complementary biophysical techniques including nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), we show that raloxifene interacts specifically with the organic component or the organic/mineral composite, and not with hydroxyapatite. Structure-activity studies reveal that the basic side chain of raloxifene is an instrumental determinant in the interaction with bone. Thus, truncation of portions of the side chain reduces bone binding and also diminishes the increase in mechanical properties. Our results support a model wherein the piperidine interacts with bone matrix through electrostatic interactions with the piperidine nitrogen and through hydrophobic interactions (van der Waals) with the aliphatic groups in the side chain and the benzothiophene core. Furthermore, in silico prediction of the potential binding sites on the surface of collagen revealed the presence of a groove with sufficient space to accommodate raloxifene analogs. The hydroxyl groups on the benzothiophene nucleus, which are necessary for binding of SERMs to the estrogen receptor, are not required for binding to the bone surface, but mediate a more robust binding of the compound to the bone powder. In conclusion, we report herein a novel property of raloxifene analogs that allows them to interact with the bone tissue through potential contacts with the organic matrix and in particular collagen.
|
Displacement of Fluormone ES2 from human recombinant full length untagged-ERalpha by fluorescence polarization competition binding assay
|
Homo sapiens
|
0.47
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of raloxifene derivatives as a selective estrogen receptor down-regulator.
Year : 2016
Volume : 24
Issue : 13
First Page : 2914
Last Page : 2919
Authors : Shoda T, Kato M, Fujisato T, Misawa T, Demizu Y, Inoue H, Naito M, Kurihara M.
Abstract : Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. A selective estrogen receptor down-regulator (SERD) that acts as not only an inhibitor of ligand binding, but also induces the down-regulation of ER, would be useful for the treatment for ER-positive breast cancer. We previously reported that tamoxifen derivatives, which have a long alkyl chain, had the ability to down-regulate ERα. With the aim of expanding range of the currently available SERDs, we designed and synthesized raloxifene derivatives, which had various lengths of the long alkyl chains, and evaluated their SERD activities. All compounds were able to bind ERα, and RC10, which has a decyl group on the amine moiety of raloxifene, was shown to be the most potent compound. Our findings suggest that the ligand core was replaceable, and that the alkyl length was important for controlling SERD activity. Moreover, RC10 showed antagonistic activity and its potency was superior to that of 4,4'-(heptane-4,4-diyl)bis(2-methylphenol) (18), a competitive antagonist of ER without SERD activity. These results provide information that will be useful for the development of promising SERDs candidates.
|
Antiproliferative activity against human MCF7:WS8 cells assessed as reduction in cell viability incubated for 5 days by Hoechst 33258 dye based assay
|
Homo sapiens
|
2.399
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer.
Year : 2019
Volume : 62
Issue : 24
First Page : 11301
Last Page : 11323
Authors : Lu Y, Gutgesell LM, Xiong R, Zhao J, Li Y, Rosales CI, Hollas M, Shen Z, Gordon-Blake J, Dye K, Wang Y, Lee S, Chen H, He D, Dubrovyskyii O, Zhao H, Huang F, Lasek AW, Tonetti DA, Thatcher GRJ.
Abstract : The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood-brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing <i>ESR1</i> mutations. A novel 3-oxyazetidine side chain was designed, leading to <b>37d</b>, a B-SERD that caused endocrine-resistant ER+ tumors to regress in a mouse orthotopic xenograft model.
|
Antagonist activity at FLAG-tagged ERalpha (unknown origin) expressed in HEK293 cells assessed as reduction in E2-induced ER-alpha-mediated transcriptional activity by luciferase reporter gene assay
|
Homo sapiens
|
0.18
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-activity relationship study of estrogen receptor down-regulators with a diphenylmethane skeleton.
Year : 2019
Volume : 27
Issue : 10
First Page : 1952
Last Page : 1961
Authors : Nanjyo S, Ohgane K, Yoshioka H, Makishima M, Hashimoto Y, Noguchi-Yachide T.
Abstract : Selective estrogen receptor (ER) down-regulators (SERDs) are pure ER antagonists that also induce ER degradation upon binding to the receptor. Although SERDs have been developed for the treatment of ER-positive breast cancers for nearly a decade, their precise mechanism(s) of action and structure-activity relationship are still unclear. Generally, Western blotting is used to examine the effects of SERDs on ER protein levels, but the methodology is low-throughput and not quantitative. Here, we describe a quantitative, high-throughput, luciferase-based assay for the evaluation of SERDs activity. For this purpose, we established stable recombinant HEK-293 cell lines expressing ERα fused with emerald luciferase. We also designed and synthesized new diphenylmethane derivatives as candidate SERDs, and evaluated their SERDs activity using the developed system in order to examine their structure-activity relationship, taking EC50 as a measure of potency, and Emax as a measure of efficacy.
|
Selective estrogen receptor down-regulator activity at FLAG-tagged ERalpha (unknown origin) expressed in HEK293 cells assessed as induction of ERalpha degradation by luciferase reporter gene assay
|
Homo sapiens
|
0.66
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-activity relationship study of estrogen receptor down-regulators with a diphenylmethane skeleton.
Year : 2019
Volume : 27
Issue : 10
First Page : 1952
Last Page : 1961
Authors : Nanjyo S, Ohgane K, Yoshioka H, Makishima M, Hashimoto Y, Noguchi-Yachide T.
Abstract : Selective estrogen receptor (ER) down-regulators (SERDs) are pure ER antagonists that also induce ER degradation upon binding to the receptor. Although SERDs have been developed for the treatment of ER-positive breast cancers for nearly a decade, their precise mechanism(s) of action and structure-activity relationship are still unclear. Generally, Western blotting is used to examine the effects of SERDs on ER protein levels, but the methodology is low-throughput and not quantitative. Here, we describe a quantitative, high-throughput, luciferase-based assay for the evaluation of SERDs activity. For this purpose, we established stable recombinant HEK-293 cell lines expressing ERα fused with emerald luciferase. We also designed and synthesized new diphenylmethane derivatives as candidate SERDs, and evaluated their SERDs activity using the developed system in order to examine their structure-activity relationship, taking EC50 as a measure of potency, and Emax as a measure of efficacy.
|
Binding affinity to human C5a assessed as dissociation constant after 1 hr by circular dichroism analysis
|
Homo sapiens
|
710.0
nM
|
|
Journal : Bioorg Med Chem
Title : A rational search for discovering potential neutraligands of human complement fragment 5a (<sup>h</sup>C5a).
Year : 2019
Volume : 27
Issue : 19
First Page : 115052
Last Page : 115052
Authors : Mishra R, Rana S.
Abstract : The human complement fragment 5a (<sup>h</sup>C5a) is an extremely potent proinflammatory glycoprotein, which upon binding to C5aR triggers a plethora of immune and non-immunological responses in humans. Dysregulation of complement system is associated with the upregulation of <sup>h</sup>C5a, leading to the surge of proinflammatory cytokines, which further exacerbate the chronic inflammation induced pathological conditions. Thus, <sup>h</sup>C5a is considered as a major pharmacological target for developing complement therapeutics that can directly or indirectly modulate the function of <sup>h</sup>C5a. However, the idea of small molecules, directly neutralizing the function of excessive <sup>h</sup>C5a remains unexplored in the literature. By recruiting cheminformatics approach, the avenue of drug repositioning is explored in the current study for discovering novel neutraligands of <sup>h</sup>C5a. The systematic exercise yields a pool of potential neutraligands, from which four FDA approved drugs, such as carprofen, oxaprozin, sulindac and raloxifene have been subjected to a battery of computational and biophysical studies against <sup>h</sup>C5a. The data obtained from docking, molecular dynamics, and molecular mechanics Poisson-Boltzmann surface area studies, strongly correlate with the data obtained from the circular dichroism, steady state fluorescence, and fluorescence quenching studies, involving the recombinant <sup>h</sup>C5a and the selected drugs. The proof of the concept study successfully documents the rational discovery of first generation template neutraligands of <sup>h</sup>C5a through drug repositioning approach and suggests that the selected drugs perhaps bind functionally distinct hot spots on <sup>h</sup>C5a. The identified neutraligands can be subsequently optimized as complement specific therapeutics for strongly modulating the <sup>h</sup>C5a-C5aR signaling axes.
|
Inhibition of aldehyde oxidase in Sprague-Dawley rat liver cytosolic fraction using methyl-nicotinamide substrate incubated for 120 mins by HPLC analysis
|
Rattus norvegicus
|
447.0
nM
|
|
Title : Therapeutic agent for nonalcoholic fatty liver disease
|
Inhibition of aldehyde oxidase in human liver cytosolic fraction using methyl-nicotinamide substrate incubated for 120 mins by HPLC analysis
|
Homo sapiens
|
44.5
nM
|
|
Title : Therapeutic agent for nonalcoholic fatty liver disease
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-0.42
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
13.99
%
|
|
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
|
13.99
%
|
|
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.
|
Antagonist activity at ER-alpha in human MCF-7:WS8 cells transfected with an estrogen response element assessed as suppression of estrogen-induced response incubated for 18 hrs by luciferase reporter gene assay
|
Homo sapiens
|
5.9
nM
|
|
Journal : J Med Chem
Title : Screening and Reverse-Engineering of Estrogen Receptor Ligands as Potent Pan-Filovirus Inhibitors.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 11085
Last Page : 11099
Authors : Cooper L,Schafer A,Li Y,Cheng H,Medegan Fagla B,Shen Z,Nowar R,Dye K,Anantpadma M,Davey RA,Thatcher GRJ,Rong L,Xiong R
Abstract : Filoviridae, including Ebola (EBOV) and Marburg (MARV) viruses, are emerging pathogens that pose a serious threat to public health. No agents have been approved to treat filovirus infections, representing a major unmet medical need. The selective estrogen receptor modulator (SERM) toremifene was previously identified from a screen of FDA-approved drugs as a potent EBOV viral entry inhibitor, via binding to EBOV glycoprotein (GP). A focused screen of ER ligands identified ridaifen-B as a potent dual inhibitor of EBOV and MARV. Optimization and reverse-engineering to remove ER activity led to a novel compound 30 (XL-147) showing potent inhibition against infectious EBOV Zaire (0.09 μM) and MARV (0.64 μM). Mutagenesis studies confirmed that inhibition of EBOV viral entry is mediated by the direct interaction with GP. Importantly, compound 30 displayed a broad-spectrum antifilovirus activity against Bundibugyo, Tai Forest, Reston, and Měnglà viruses and is the first submicromolar antiviral agent reported for some of these strains, therefore warranting further development as a pan-filovirus inhibitor.
|
Induction of mitochondrial membrane damage in human MCF7 cells assessed as reduction in mitochondrial membrane potential at 50 uM incubated for 1 hr by TMRE dye based fluorometric analysis relative to control
|
Homo sapiens
|
10.0
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol.
Year : 2021
Volume : 30
First Page : 115957
Last Page : 115957
Authors : Pugachev MV,Pavelyev RS,Nguyen TNT,Gabbasova RR,Bulatov TM,Iksanova AG,Aljondi B,Bondar OV,Grishaev DY,Yamaleeva ZR,Kataeva ON,Nikishova TV,Balakin KV,Shtyrlin YG
Abstract : A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC < 10 μM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC < 5 μM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.
|
Induction of mitochondrial membrane damage in human MCF7 cells assessed as reduction in mitochondrial membrane potential at 100 uM incubated for 1 hr by TMRE dye based fluorometric analysis relative to control
|
Homo sapiens
|
20.0
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol.
Year : 2021
Volume : 30
First Page : 115957
Last Page : 115957
Authors : Pugachev MV,Pavelyev RS,Nguyen TNT,Gabbasova RR,Bulatov TM,Iksanova AG,Aljondi B,Bondar OV,Grishaev DY,Yamaleeva ZR,Kataeva ON,Nikishova TV,Balakin KV,Shtyrlin YG
Abstract : A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC < 10 μM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC < 5 μM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.
|
Induction of mitochondrial membrane damage in human MDA-MB-231 cells assessed as reduction in mitochondrial membrane potential at 100 uM incubated for 1 hr by TMRE dye based fluorometric analysis relative to control
|
Homo sapiens
|
9.0
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol.
Year : 2021
Volume : 30
First Page : 115957
Last Page : 115957
Authors : Pugachev MV,Pavelyev RS,Nguyen TNT,Gabbasova RR,Bulatov TM,Iksanova AG,Aljondi B,Bondar OV,Grishaev DY,Yamaleeva ZR,Kataeva ON,Nikishova TV,Balakin KV,Shtyrlin YG
Abstract : A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC < 10 μM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC < 5 μM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.
|
Induction of mitochondrial membrane damage in human MCF7 cells assessed as reduction in mitochondrial membrane potential at IC50 incubated for 72 hrs by TMRE dye based fluorometric analysis relative to control
|
Homo sapiens
|
33.0
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol.
Year : 2021
Volume : 30
First Page : 115957
Last Page : 115957
Authors : Pugachev MV,Pavelyev RS,Nguyen TNT,Gabbasova RR,Bulatov TM,Iksanova AG,Aljondi B,Bondar OV,Grishaev DY,Yamaleeva ZR,Kataeva ON,Nikishova TV,Balakin KV,Shtyrlin YG
Abstract : A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC < 10 μM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC < 5 μM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.
|
Induction of mitochondrial membrane damage in human MDA-MB-231 cells assessed as reduction in mitochondrial membrane potential at IC50 incubated for 72 hrs by TMRE dye based fluorometric analysis relative to control
|
Homo sapiens
|
22.0
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol.
Year : 2021
Volume : 30
First Page : 115957
Last Page : 115957
Authors : Pugachev MV,Pavelyev RS,Nguyen TNT,Gabbasova RR,Bulatov TM,Iksanova AG,Aljondi B,Bondar OV,Grishaev DY,Yamaleeva ZR,Kataeva ON,Nikishova TV,Balakin KV,Shtyrlin YG
Abstract : A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC < 10 μM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC < 5 μM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.
|
Downregulation of ERalpha expression in human MCF7 cells at IC50 incubated for 72 hrs by Western blot assay
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol.
Year : 2021
Volume : 30
First Page : 115957
Last Page : 115957
Authors : Pugachev MV,Pavelyev RS,Nguyen TNT,Gabbasova RR,Bulatov TM,Iksanova AG,Aljondi B,Bondar OV,Grishaev DY,Yamaleeva ZR,Kataeva ON,Nikishova TV,Balakin KV,Shtyrlin YG
Abstract : A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC < 10 μM were also tested for cytotoxicity in vitro against MDA-MB-231 (ER-) breast adenocarcinoma cells and conditionally normal human skin fibroblasts (HSF). The patterns of structure-antitumor activity relationships of the obtained compounds were analyzed. The most active compounds were found to contain a six-membered ketal ring, a methyl group in position 5, a 3,4-dimethoxystyryl fragment in positions 2 or 6 of the pyridoxine ring, and a trans-configuration of the double bond. Using the most active compound 5a as a representative cytotoxic agent, we have demonstrated that it has high specificity and antiproliferative activity against MCF-7 (ER+) tumor cells (IC < 5 μM), and a higher therapeutic index compared to the reference compound raloxifene (48 versus 5.8). Compound 5a decreased the mitochondrial membrane potential and increased the level of reactive oxygen species in MCF-7 cells, but not MDA-MB-231 cells. Compound 5a did not affect the distribution of cell cycle phases and induced apoptosis in MCF-7 cells, but not MDA-MB-231. Unlike compound 5a, raloxifene decreased mitochondrial potential, increased the ROS level, and induced apoptosis in both MCF-7 and MDA-MB-231 cells, which indicated a lack of selectivity for cells with estrogen receptor expression. It was also shown that compound 5a reduced the level of ERα expression in cells to a lesser extent than raloxifene and, unlike the latter, did not activate the PI3K/Akt signaling pathway.
|
Inhibition of ERalpha (unknown origin) at 1 uM by fluorescence polarization assay relative to control
|
Homo sapiens
|
74.81
%
|
|
|
Displacement of fluorescent estradiol from recombinant ERalpha (unknown origin) at 1 uM measured after 2 hrs by fluorescence polarization assay
|
Homo sapiens
|
74.81
%
|
|
|
Uncompetitive type inhibition of human AOX assessed as inhibition constant using phthalazine as substrate preincubated for 30 mins followed by substrate addition by HPLC-MS analysis
|
Homo sapiens
|
0.87
nM
|
|
|
Uncompetitive type inhibition of human AOX assessed as inhibition constant using vanillin as substrate by HPLC-MS analysis
|
Homo sapiens
|
0.87
nM
|
|
|
Uncompetitive type inhibition of human AOX assessed as inhibition constant using nicotine-1(S)-iminium ion as substrate incubated for 2 mins by HPLC-MS analysis
|
Homo sapiens
|
0.87
nM
|
|
