|
Antagonist dissociation constant in dog prostate
|
Canis lupus familiaris
|
25.7
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
Year : 2000
Volume : 43
Issue : 8
First Page : 1586
Last Page : 1603
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I.
Abstract : In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
|
Antagonist dissociation constant in rat spleen
|
Rattus norvegicus
|
0.309
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
Year : 2000
Volume : 43
Issue : 8
First Page : 1586
Last Page : 1603
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I.
Abstract : In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
|
Antagonist dissociation constant in rat vas deferens
|
Rattus norvegicus
|
2.042
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
Year : 2000
Volume : 43
Issue : 8
First Page : 1586
Last Page : 1603
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I.
Abstract : In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
|
In vitro antagonistic activity against alpha-1B receptor in rat spleen.
|
Rattus norvegicus
|
0.309
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.
Year : 2001
Volume : 44
Issue : 12
First Page : 1971
Last Page : 1985
Authors : Meyer MD, Altenbach RJ, Bai H, Basha FZ, Carroll WA, Kerwin JF, Lebold SA, Lee E, Pratt JK, Sippy KB, Tietje K, Wendt MD, Brune ME, Buckner SA, Hancock AA, Drizin I.
Abstract : In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
|
Compound was tested for its binding affinity for alpha-1 adrenergic receptor site by displacement of [3H]clonidine at 10e-6 M concentration
|
None
|
2.2
nM
|
|
Compound was tested for its binding affinity for alpha-1 adrenergic receptor site by displacement of [3H]clonidine at 10e-6 M concentration
|
None
|
1.1
nM
|
|
Compound was tested for its binding affinity for alpha-1 adrenergic receptor site by displacement of [3H]clonidine at 10e-6 M concentration
|
None
|
2.6
nM
|
|
Journal : J. Med. Chem.
Title : 2,4-diamino-6,7-dimethoxyquinazolines. 1. 2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1-yl] derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents.
Year : 1987
Volume : 30
Issue : 1
First Page : 49
Last Page : 57
Authors : Campbell SF, Davey MJ, Hardstone JD, Lewis BN, Palmer MJ.
Abstract : A series of 4-amino-2-[4-(1,4-benzodioxan-2-ylcarbonyl)piperazin-1 -yl]-6, 7-dimethoxyquinazoline derivatives was synthesized for evaluation as alpha-antagonists and antihypertensive agents. Most compounds displayed high (nM) binding affinity for alpha 1-adrenoceptors with no significant activity at alpha 2-sites. Selective antagonism of the alpha 1-mediated vasoconstrictor effects of norepinephrine is also characteristic of the series. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented, and structural similarity between the 2,4-diamino-6,7-dimethoxyquinazoline nucleus and norepinephrine is established. An alpha 1-receptor model is presented in which charge-reinforced hydrogen bonding is important for binding of both antagonist and agonist molecules. Antihypertensive activity was evaluated after oral administration (5 mg/kg) to spontaneously hypertensive rats, and several compounds displayed similar efficacy to prazosin when assessed after 6 h. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compound 1 (doxazosin) was selected for further evaluation and is currently progressing through phase III clinical trials.
|
Binding affinity against Alpha-1D adrenergic receptor, from human clones.
|
Homo sapiens
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity was tested on human Alpha-1D adrenergic receptor
|
None
|
3.981
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacological options in the treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 9
First Page : 1293
Last Page : 1315
Authors : Kenny B, Ballard S, Blagg J, Fox D.
|
Binding affinity against Alpha-2A adrenergic receptor, from human clones.
|
Homo sapiens
|
729.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
pA2 for Alpha-1 adrenergic receptor from human prostate.
|
None
|
6.31
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacological options in the treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 9
First Page : 1293
Last Page : 1315
Authors : Kenny B, Ballard S, Blagg J, Fox D.
|
Binding affinity against Alpha-2C adrenergic receptor from human clones.
|
Homo sapiens
|
280.0
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
In vitro antagonistic activity against alpha-1A receptor in dog prostate.
|
Canis lupus familiaris
|
25.7
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.
Year : 2001
Volume : 44
Issue : 12
First Page : 1971
Last Page : 1985
Authors : Meyer MD, Altenbach RJ, Bai H, Basha FZ, Carroll WA, Kerwin JF, Lebold SA, Lee E, Pratt JK, Sippy KB, Tietje K, Wendt MD, Brune ME, Buckner SA, Hancock AA, Drizin I.
Abstract : In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
|
Binding affinity against Alpha-1A adrenergic receptor from human clone
|
Homo sapiens
|
2.6
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity was tested on human Alpha-1A adrenergic receptor
|
None
|
3.162
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacological options in the treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 9
First Page : 1293
Last Page : 1315
Authors : Kenny B, Ballard S, Blagg J, Fox D.
|
In vitro antagonistic activity towards alpha-1A adrenergic receptor in rat vas deferens
|
Rattus norvegicus
|
2.042
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.
Year : 2001
Volume : 44
Issue : 12
First Page : 1971
Last Page : 1985
Authors : Meyer MD, Altenbach RJ, Bai H, Basha FZ, Carroll WA, Kerwin JF, Lebold SA, Lee E, Pratt JK, Sippy KB, Tietje K, Wendt MD, Brune ME, Buckner SA, Hancock AA, Drizin I.
Abstract : In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
|
Binding affinity against Alpha-1B adrenergic receptor from human clone
|
Homo sapiens
|
0.74
nM
|
|
Journal : J. Med. Chem.
Title : Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Year : 1995
Volume : 38
Issue : 18
First Page : 3415
Last Page : 3444
Authors : Hieble JP, Bondinell WE, Ruffolo RR.
|
Binding affinity was tested on human Alpha-1B adrenergic receptor
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacological options in the treatment of benign prostatic hyperplasia.
Year : 1997
Volume : 40
Issue : 9
First Page : 1293
Last Page : 1315
Authors : Kenny B, Ballard S, Blagg J, Fox D.
|
In vivo antagonist dissociation constant in intaraurethral pressure model in dogs.
|
Canis lupus familiaris
|
75.86
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.
Year : 2001
Volume : 44
Issue : 12
First Page : 1971
Last Page : 1985
Authors : Meyer MD, Altenbach RJ, Bai H, Basha FZ, Carroll WA, Kerwin JF, Lebold SA, Lee E, Pratt JK, Sippy KB, Tietje K, Wendt MD, Brune ME, Buckner SA, Hancock AA, Drizin I.
Abstract : In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
|
Intraurethral pressure (IUP) in Beagle dogs values are expressed as pseudo pA2 values.
|
Canis lupus familiaris
|
75.86
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).
Year : 2000
Volume : 43
Issue : 8
First Page : 1586
Last Page : 1603
Authors : Meyer MD, Altenbach RJ, Basha FZ, Carroll WA, Condon S, Elmore SW, Kerwin JF, Sippy KB, Tietje K, Wendt MD, Hancock AA, Brune ME, Buckner SA, Drizin I.
Abstract : In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
|
Displacement of [3H]prazosin from cloned human ADRA1A expressed in CHO cells
|
Homo sapiens
|
0.537
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships in 1,4-benzodioxan-related compounds. 8.(1) {2-[2-(4-chlorobenzyloxy)phenoxy]ethyl}-[2-(2,6-dimethoxyphenoxy)ethyl]amine (clopenphendioxan) as a tool to highlight the involvement of alpha1D- and alpha1B-adrenoreceptor subtypes in the regulation of human PC-3 prostate cancer cell apoptosis and proliferation.
Year : 2005
Volume : 48
Issue : 24
First Page : 7750
Last Page : 7763
Authors : Quaglia W, Santoni G, Pigini M, Piergentili A, Gentili F, Buccioni M, Mosca M, Lucciarini R, Amantini C, Nabissi MI, Ballarini P, Poggesi E, Leonardi A, Giannella M.
Abstract : A series of new alpha1-adrenoreceptor antagonists (5-18) was prepared by introducing various substituents (Topliss approach) into the ortho, meta, and para positions of the benzyloxy function of the phendioxan open analogue 4 ("openphendioxan"). All the compounds synthesized were potent antagonists and generally displayed, similarly to 4, the highest affinity values at alpha1D- with respect to alpha1A- and alpha1B-AR subtypes and 5-HT1A subtype. By sulforhodamine B (SRB) assay on human PC-3 prostate cancer cells, the new compounds showed antitumor activity (estimated on the basis of three parameters GI50, TGI, LC50), at low micromolar concentration, with 7 ("clopenphendioxan") exhibiting the highest efficacy. Moreover, this study highlighted for the first time alpha1D- and alpha1B-AR expression in PC3 cells and also demonstrated the involvement of these subtypes in the modulation of apoptosis and cell proliferation. A significant reduction of alpha1D- and alpha1B-AR expression in PC3 cells was associated with the apoptosis induced by 7. This depletion was completely reversed by norepinephrine.
|
Displacement of [3H]prazosin from cloned human ADRA1B expressed in CHO cells
|
Homo sapiens
|
0.8128
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships in 1,4-benzodioxan-related compounds. 8.(1) {2-[2-(4-chlorobenzyloxy)phenoxy]ethyl}-[2-(2,6-dimethoxyphenoxy)ethyl]amine (clopenphendioxan) as a tool to highlight the involvement of alpha1D- and alpha1B-adrenoreceptor subtypes in the regulation of human PC-3 prostate cancer cell apoptosis and proliferation.
Year : 2005
Volume : 48
Issue : 24
First Page : 7750
Last Page : 7763
Authors : Quaglia W, Santoni G, Pigini M, Piergentili A, Gentili F, Buccioni M, Mosca M, Lucciarini R, Amantini C, Nabissi MI, Ballarini P, Poggesi E, Leonardi A, Giannella M.
Abstract : A series of new alpha1-adrenoreceptor antagonists (5-18) was prepared by introducing various substituents (Topliss approach) into the ortho, meta, and para positions of the benzyloxy function of the phendioxan open analogue 4 ("openphendioxan"). All the compounds synthesized were potent antagonists and generally displayed, similarly to 4, the highest affinity values at alpha1D- with respect to alpha1A- and alpha1B-AR subtypes and 5-HT1A subtype. By sulforhodamine B (SRB) assay on human PC-3 prostate cancer cells, the new compounds showed antitumor activity (estimated on the basis of three parameters GI50, TGI, LC50), at low micromolar concentration, with 7 ("clopenphendioxan") exhibiting the highest efficacy. Moreover, this study highlighted for the first time alpha1D- and alpha1B-AR expression in PC3 cells and also demonstrated the involvement of these subtypes in the modulation of apoptosis and cell proliferation. A significant reduction of alpha1D- and alpha1B-AR expression in PC3 cells was associated with the apoptosis induced by 7. This depletion was completely reversed by norepinephrine.
|
Displacement of [3H]prazosin from cloned human ADRA1D expressed in CHO cells
|
Homo sapiens
|
0.8128
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships in 1,4-benzodioxan-related compounds. 8.(1) {2-[2-(4-chlorobenzyloxy)phenoxy]ethyl}-[2-(2,6-dimethoxyphenoxy)ethyl]amine (clopenphendioxan) as a tool to highlight the involvement of alpha1D- and alpha1B-adrenoreceptor subtypes in the regulation of human PC-3 prostate cancer cell apoptosis and proliferation.
Year : 2005
Volume : 48
Issue : 24
First Page : 7750
Last Page : 7763
Authors : Quaglia W, Santoni G, Pigini M, Piergentili A, Gentili F, Buccioni M, Mosca M, Lucciarini R, Amantini C, Nabissi MI, Ballarini P, Poggesi E, Leonardi A, Giannella M.
Abstract : A series of new alpha1-adrenoreceptor antagonists (5-18) was prepared by introducing various substituents (Topliss approach) into the ortho, meta, and para positions of the benzyloxy function of the phendioxan open analogue 4 ("openphendioxan"). All the compounds synthesized were potent antagonists and generally displayed, similarly to 4, the highest affinity values at alpha1D- with respect to alpha1A- and alpha1B-AR subtypes and 5-HT1A subtype. By sulforhodamine B (SRB) assay on human PC-3 prostate cancer cells, the new compounds showed antitumor activity (estimated on the basis of three parameters GI50, TGI, LC50), at low micromolar concentration, with 7 ("clopenphendioxan") exhibiting the highest efficacy. Moreover, this study highlighted for the first time alpha1D- and alpha1B-AR expression in PC3 cells and also demonstrated the involvement of these subtypes in the modulation of apoptosis and cell proliferation. A significant reduction of alpha1D- and alpha1B-AR expression in PC3 cells was associated with the apoptosis induced by 7. This depletion was completely reversed by norepinephrine.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
85.6
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Displacement of [3H]prazosin from human alpha1A adrenoceptor expressed in CHO cells
|
Homo sapiens
|
0.537
nM
|
|
Journal : J. Med. Chem.
Title : Doxazosin-related alpha1-adrenoceptor antagonists with prostate antitumor activity.
Year : 2009
Volume : 52
Issue : 15
First Page : 4951
Last Page : 4954
Authors : Giardinà D, Martarelli D, Sagratini G, Angeli P, Ballinari D, Gulini U, Melchiorre C, Poggesi E, Pompei P.
Abstract : Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and in vivo, respectively. Because of its antitumor efficacy at low concentrations, lower apoptotic activity in NHDF vs tumor cells, and antiangiogenetic effect, 1 showed a better therapeutic profile relative to doxazosin.
|
Displacement of [3H]prazosin from human Alpha-1B adrenoceptor expressed in CHO cells
|
Homo sapiens
|
0.8128
nM
|
|
Journal : J. Med. Chem.
Title : Doxazosin-related alpha1-adrenoceptor antagonists with prostate antitumor activity.
Year : 2009
Volume : 52
Issue : 15
First Page : 4951
Last Page : 4954
Authors : Giardinà D, Martarelli D, Sagratini G, Angeli P, Ballinari D, Gulini U, Melchiorre C, Poggesi E, Pompei P.
Abstract : Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and in vivo, respectively. Because of its antitumor efficacy at low concentrations, lower apoptotic activity in NHDF vs tumor cells, and antiangiogenetic effect, 1 showed a better therapeutic profile relative to doxazosin.
|
Displacement of [3H]prazosin from human Alpha-1D adrenoceptor expressed in CHO cells
|
Homo sapiens
|
0.8128
nM
|
|
Journal : J. Med. Chem.
Title : Doxazosin-related alpha1-adrenoceptor antagonists with prostate antitumor activity.
Year : 2009
Volume : 52
Issue : 15
First Page : 4951
Last Page : 4954
Authors : Giardinà D, Martarelli D, Sagratini G, Angeli P, Ballinari D, Gulini U, Melchiorre C, Poggesi E, Pompei P.
Abstract : Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and in vivo, respectively. Because of its antitumor efficacy at low concentrations, lower apoptotic activity in NHDF vs tumor cells, and antiangiogenetic effect, 1 showed a better therapeutic profile relative to doxazosin.
|
Antagonist activity at rat alpha1A adrenoceptor assessed as inhibition if norepinephrine-induced contraction of vas deference
|
Rattus norvegicus
|
2.042
nM
|
|
Journal : J. Med. Chem.
Title : Doxazosin-related alpha1-adrenoceptor antagonists with prostate antitumor activity.
Year : 2009
Volume : 52
Issue : 15
First Page : 4951
Last Page : 4954
Authors : Giardinà D, Martarelli D, Sagratini G, Angeli P, Ballinari D, Gulini U, Melchiorre C, Poggesi E, Pompei P.
Abstract : Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and in vivo, respectively. Because of its antitumor efficacy at low concentrations, lower apoptotic activity in NHDF vs tumor cells, and antiangiogenetic effect, 1 showed a better therapeutic profile relative to doxazosin.
|
Antagonist activity at rat Alpha-1B adrenoceptor assessed as inhibition if phenylephrine-induced contraction of spleen
|
Rattus norvegicus
|
0.309
nM
|
|
Journal : J. Med. Chem.
Title : Doxazosin-related alpha1-adrenoceptor antagonists with prostate antitumor activity.
Year : 2009
Volume : 52
Issue : 15
First Page : 4951
Last Page : 4954
Authors : Giardinà D, Martarelli D, Sagratini G, Angeli P, Ballinari D, Gulini U, Melchiorre C, Poggesi E, Pompei P.
Abstract : Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and in vivo, respectively. Because of its antitumor efficacy at low concentrations, lower apoptotic activity in NHDF vs tumor cells, and antiangiogenetic effect, 1 showed a better therapeutic profile relative to doxazosin.
|
Antagonist activity at rat Alpha-1D adrenoceptor assessed as inhibition if norepenephrine-induced contraction of thoracic aorta
|
Rattus norvegicus
|
1.072
nM
|
|
Journal : J. Med. Chem.
Title : Doxazosin-related alpha1-adrenoceptor antagonists with prostate antitumor activity.
Year : 2009
Volume : 52
Issue : 15
First Page : 4951
Last Page : 4954
Authors : Giardinà D, Martarelli D, Sagratini G, Angeli P, Ballinari D, Gulini U, Melchiorre C, Poggesi E, Pompei P.
Abstract : Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and in vivo, respectively. Because of its antitumor efficacy at low concentrations, lower apoptotic activity in NHDF vs tumor cells, and antiangiogenetic effect, 1 showed a better therapeutic profile relative to doxazosin.
|
Inhibition of human ERG
|
Homo sapiens
|
588.84
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Predicting hERG activities of compounds from their 3D structures: development and evaluation of a global descriptors based QSAR model.
Year : 2011
Volume : 46
Issue : 2
First Page : 618
Last Page : 630
Authors : Sinha N, Sen S.
Abstract : A QSAR based predictive model of hERG activity in terms of 'global descriptors' has been developed and evaluated. The QSAR was developed by training 77 compounds covering a wide range of activities and was validated based on an external 'test set' of 80 compounds using neural network method. Statistical parameters and examination of enrichment factor indicated the effectiveness of the present model. Randomization test demonstrated the robustness of the model and cross-validation test further validated the QSAR. Domain of applicability test indicated to the high degree of reliability of the predicted results. Satisfactory performance in classifying compounds into 'active' and 'inactive' groups was also obtained. The cases where the QSAR failed, the possible sources of errors have been discussed.
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
1.551
nM
|
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
0.628
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-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
0.751
nM
|
|
DRUGMATRIX: Alpha-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
0.416
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
|
3.383
nM
|
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
1.663
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
|
368.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
234.0
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
|
544.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2C radioligand binding (ligand: [3H] Mesulergine)
|
None
|
285.0
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-HT4 radioligand binding (ligand: [3H] GR-113808)
|
Cavia porcellus
|
764.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT4 radioligand binding (ligand: [3H] GR-113808)
|
Cavia porcellus
|
127.0
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 Transporter radioligand binding (ligand: [125I] RTI-55)
|
None
|
188.0
nM
|
|
DRUGMATRIX: Dopamine Transporter radioligand binding (ligand: [125I] RTI-55)
|
None
|
149.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
28.8
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-17.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
45.8
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
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
|
-13.0
%
|
|
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
|
102.0
%
|
|
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.
|
Displacement of [3H]prazosin from human alpha1A adrenoceptor expressed in CHO cell membranes after 30 mins
|
Homo sapiens
|
0.7762
nM
|
|
Journal : Eur J Med Chem
Title : Quinazoline based α1-adrenoreceptor antagonists with potent antiproliferative activity in human prostate cancer cell lines.
Year : 2017
Volume : 136
First Page : 259
Last Page : 269
Authors : Maestri V, Tarozzi A, Simoni E, Cilia A, Poggesi E, Naldi M, Nicolini B, Pruccoli L, Rosini M, Minarini A.
Abstract : New α1-adrenoreceptor (α1-AR) antagonists related to prazosin and doxazosin were synthesized by replacing piperazine ring with (S)- or (R)-3-aminopiperidine. Binding studies indicated that the S configuration at the 3-C position of the piperidine ring is crucial for an optimal interaction of the compounds at all three α1-AR subtypes. Quinazolines 9 and 10, bearing a quinone ring on the lateral chain, exhibited also potent antiproliferative activity in LNCaP androgen-sensitive prostate cancer cell lines, higher than that of doxazosin. Compound 10 increased apoptosis, in terms of DNA fragmentation, without triggering cell necrosis. The prooxidant activity found in compound 10 may underlie its ability to inhibit cell proliferation in synergy with the effect mediated by α1-AR antagonism. Due to its better biological profile compared to doxazosin for LNCaP cell line, compound 10 might be a valuable lead compound for the design of new prostate antitumor agents.
|
Displacement of [3H]prazosin from human alpha1B adrenoceptor expressed in CHO cell membranes after 30 mins
|
Homo sapiens
|
0.631
nM
|
|
Journal : Eur J Med Chem
Title : Quinazoline based α1-adrenoreceptor antagonists with potent antiproliferative activity in human prostate cancer cell lines.
Year : 2017
Volume : 136
First Page : 259
Last Page : 269
Authors : Maestri V, Tarozzi A, Simoni E, Cilia A, Poggesi E, Naldi M, Nicolini B, Pruccoli L, Rosini M, Minarini A.
Abstract : New α1-adrenoreceptor (α1-AR) antagonists related to prazosin and doxazosin were synthesized by replacing piperazine ring with (S)- or (R)-3-aminopiperidine. Binding studies indicated that the S configuration at the 3-C position of the piperidine ring is crucial for an optimal interaction of the compounds at all three α1-AR subtypes. Quinazolines 9 and 10, bearing a quinone ring on the lateral chain, exhibited also potent antiproliferative activity in LNCaP androgen-sensitive prostate cancer cell lines, higher than that of doxazosin. Compound 10 increased apoptosis, in terms of DNA fragmentation, without triggering cell necrosis. The prooxidant activity found in compound 10 may underlie its ability to inhibit cell proliferation in synergy with the effect mediated by α1-AR antagonism. Due to its better biological profile compared to doxazosin for LNCaP cell line, compound 10 might be a valuable lead compound for the design of new prostate antitumor agents.
|
Displacement of [3H]prazosin from human alpha1D adrenoceptor expressed in CHO cell membranes after 30 mins
|
Homo sapiens
|
0.3236
nM
|
|
Journal : Eur J Med Chem
Title : Quinazoline based α1-adrenoreceptor antagonists with potent antiproliferative activity in human prostate cancer cell lines.
Year : 2017
Volume : 136
First Page : 259
Last Page : 269
Authors : Maestri V, Tarozzi A, Simoni E, Cilia A, Poggesi E, Naldi M, Nicolini B, Pruccoli L, Rosini M, Minarini A.
Abstract : New α1-adrenoreceptor (α1-AR) antagonists related to prazosin and doxazosin were synthesized by replacing piperazine ring with (S)- or (R)-3-aminopiperidine. Binding studies indicated that the S configuration at the 3-C position of the piperidine ring is crucial for an optimal interaction of the compounds at all three α1-AR subtypes. Quinazolines 9 and 10, bearing a quinone ring on the lateral chain, exhibited also potent antiproliferative activity in LNCaP androgen-sensitive prostate cancer cell lines, higher than that of doxazosin. Compound 10 increased apoptosis, in terms of DNA fragmentation, without triggering cell necrosis. The prooxidant activity found in compound 10 may underlie its ability to inhibit cell proliferation in synergy with the effect mediated by α1-AR antagonism. Due to its better biological profile compared to doxazosin for LNCaP cell line, compound 10 might be a valuable lead compound for the design of new prostate antitumor agents.
|
Displacement of [3H]-prazosin from rat alpha1A adrenergic receptor after 60 mins by scintillation counting analysis
|
Rattus norvegicus
|
0.74
nM
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of small molecule agonists of EphA2 receptor.
Year : 2018
Volume : 143
First Page : 1261
Last Page : 1276
Authors : Petty A, Idippily N, Bobba V, Geldenhuys WJ, Zhong B, Su B, Wang B.
Abstract : Ligand-independent activation of EphA2 receptor kinase promotes cancer metastasis and invasion. Activating EphA2 receptor tyrosine kinase with small molecule agonist is a novel strategy to treat EphA2 overexpressing cancer. In this study, we performed a lead optimization of a small molecule Doxazosin that was identified as an EphA2 receptor agonist. 33 new analogs were developed and evaluated; a structure-activity relationship was summarized based on the EphA2 activation of these derivatives. Two new derivative compounds 24 and 27 showed much improved activity compared to Doxazosin. Compound 24 possesses a bulky amide moiety, and compound 27 has a dimeric structure that is very different to the parental compound. Compound 27 with a twelve-carbon linker of the dimer activated the kinase and induced receptor internalization and cell death with the best potency. Another dimer with a six-carbon linker has significantly reduced potency compared to the dimer with a longer linker, suggesting that the length of the linker is critical for the activity of the dimeric agonist. To explore the receptor binding characteristics of the new molecules, we applied a docking study to examine how the small molecule binds to the EphA2 receptor. The results reveal that compounds 24 and 27 form more hydrogen bonds to EphA2 than Doxazosin, suggesting that they may have higher binding affinity to the receptor.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
8.23
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
5.29
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
13.22
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
9.67
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
24.9
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
3.14
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
2.35
%
|
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
16.4
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.18
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.18
%
|
|
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.
