|
Inhibitory activity against 5-hydroxytryptamine 2 receptor by 3H ligand binding experiments.
|
None
|
9.8
nM
|
|
Journal : J. Med. Chem.
Title : Novel benzamides as selective and potent gastrokinetic agents. 2. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl] benzamide citrate (AS-4370) and related compounds.
Year : 1991
Volume : 34
Issue : 2
First Page : 616
Last Page : 624
Authors : Kato S, Morie T, Kon T, Yoshida N, Karasawa T, Matsumoto J.
Abstract : The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.
|
Compound was evaluated for the binding affinity at 5- HT2 receptor
|
None
|
7.2
nM
|
|
Journal : J. Med. Chem.
Title : The serotonin 5-HT4 receptor. 1. Design of a new class of agonists and receptor map of the agonist recognition site.
Year : 1995
Volume : 38
Issue : 13
First Page : 2326
Last Page : 2330
Authors : Buchheit KH, Gamse R, Giger R, Hoyer D, Klein F, Klöppner E, Pfannkuche HJ, Mattes H.
Abstract : The design and synthesis of a new class of potent and selective 5-HT4 receptor agonists containing an indole nucleus linked to a carbazimidamide are presented. A conformational study of the 5-HT4 receptor agonists serotonin and zacopride led to the identification of an initial pharmacophore and to the definition of a three-dimensional map of the 5-HT4 agonist recognition site. 1, a representative member of our new class of 5-HT4 receptor agonists, incorporates all reference structural features and matched perfectly with these models. 1 is a highly potent, full agonist at 5-HT4 receptors present in the isolated electrically stimulated guinea pig ileum preparation, with a pD2 value of 8.8, displaying selectivity (ranging from 40- to over 10,000-fold) versus other members of the serotonin receptor family.
|
The ability to inhibit [3H]ketanserin binding to 5-hydroxytryptamine 2 receptor in rat whole brain
|
None
|
6.1
nM
|
|
Journal : J. Med. Chem.
Title : SC-53116: the first selective agonist at the newly identified serotonin 5-HT4 receptor subtype.
Year : 1992
Volume : 35
Issue : 8
First Page : 1486
Last Page : 1489
Authors : Flynn DL, Zabrowski DL, Becker DP, Nosal R, Villamil CI, Gullikson GW, Moummi C, Yang DC.
|
Inhibition of [3H]GR-65630 binding to 5-hydroxytryptamine 3 receptor
|
Rattus norvegicus
|
134.0
nM
|
|
Journal : J. Med. Chem.
Title : SC-53116: the first selective agonist at the newly identified serotonin 5-HT4 receptor subtype.
Year : 1992
Volume : 35
Issue : 8
First Page : 1486
Last Page : 1489
Authors : Flynn DL, Zabrowski DL, Becker DP, Nosal R, Villamil CI, Gullikson GW, Moummi C, Yang DC.
|
Antagonistic activity against Serotonin 5-hydroxytryptamine 3 receptor of isolated guinea pig ileum (GPI)
|
Cavia porcellus
|
63.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel ligands for the 5-HT3 and the 5-HT4 receptor
Year : 1992
Volume : 2
Issue : 5
First Page : 461
Last Page : 466
Authors : Blum E, Buchheit K, Buescher H, Gamse R, Kloeppner E, Meigel H, Papageorgiou C, Waelchli R, Revesz L
|
Evaluated for the antagonistic activity against Serotonin 5-hydroxytryptamine 3 receptor in isolated perfused rabbit heart (RH)
|
Oryctolagus cuniculus
|
79.43
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel ligands for the 5-HT3 and the 5-HT4 receptor
Year : 1992
Volume : 2
Issue : 5
First Page : 461
Last Page : 466
Authors : Blum E, Buchheit K, Buescher H, Gamse R, Kloeppner E, Meigel H, Papageorgiou C, Waelchli R, Revesz L
|
Antagonistic activity against Serotonin 5-hydroxytryptamine 3 receptor in isolated rabbit vagus nerve (RVN)
|
Oryctolagus cuniculus
|
316.23
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel ligands for the 5-HT3 and the 5-HT4 receptor
Year : 1992
Volume : 2
Issue : 5
First Page : 461
Last Page : 466
Authors : Blum E, Buchheit K, Buescher H, Gamse R, Kloeppner E, Meigel H, Papageorgiou C, Waelchli R, Revesz L
|
Inhibition of [3H]BRL-43694 binding to rat 5-hydroxytryptamine 3 receptor
|
Rattus norvegicus
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives with 5-HT3 antagonist and 5-HT4 agonist properties.
Year : 1994
Volume : 37
Issue : 9
First Page : 1320
Last Page : 1325
Authors : Monge A, Peña MC, Palop JA, Calderó JM, Roca J, García E, Romero G, del Río J, Lasheras B.
Abstract : New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2e and 2f, were more potent than ondansetron in this regard. However, these two compounds were much weaker than the typical 5-HT3 receptor antagonist as displacers of [3H]BRL-43694 binding to rat cerebral cortex homogenates or as antagonists of the bradycardia response to 5-HT in the anaesthetized rat. Like the prokinetic agent cisapride, some of the new compounds enhanced gastric emptying in rats. Compound 2f not only markedly enhanced gastric emptying but was also a potent agonist at the isolated rat oesophageal tunica muscularis mucosae, a preparation sensitive to 5-HT4 receptor stimulation, and enhanced the twitch response in the LMMP preparation. The latter effect was blocked by a high concentration of tropisetron or by previous desensitization with 5-methoxytryptamine. Compound 2f appears to show a promising pharmacological profile as a potential gastrokinetic agent.
|
Inhibition of [3H]GR-65630 binding to rat cortical membrane serotonin 5-hydroxytryptamine 3 receptor
|
Rattus norvegicus
|
94.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
Inhibition of [3H]GR-113808 binding to guinea pig striatum 5-hydroxytryptamine 4 receptor
|
Cavia porcellus
|
14.3
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
Compound was evaluated for the agonistic activity towards 5-hydroxytryptamine 4 receptor using the rat tunica muscularis mucosae (TMM) esophagus strip assay
|
None
|
55.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New aza(nor)adamantanes are agonists at the newly identified serotonin 5-HT4 receptor and antagonists at the 5-HT3 receptor
Year : 1992
Volume : 2
Issue : 12
First Page : 1613
Last Page : 1618
Authors : Flynn DL, Becker DP, Spangler DP, Nosal R, Gullikson GW, Moummi C, Yang D
|
Compound was tested for 5-hydroxytryptamine 3 receptor binding affinity
|
None
|
152.0
nM
|
|
Journal : J. Med. Chem.
Title : 5-HT4 receptor ligands: applications and new prospects.
Year : 2003
Volume : 46
Issue : 3
First Page : 319
Last Page : 344
Authors : Langlois M, Fischmeister R.
|
Binding affinity towards Serotonin 5-hydroxytryptamine 4 receptor
|
None
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior.
Year : 2003
Volume : 46
Issue : 11
First Page : 2017
Last Page : 2022
Authors : Pearlstein R, Vaz R, Rampe D.
|
Compound was evaluated for the binding affinity at Alpha adrenergic receptor
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : The serotonin 5-HT4 receptor. 1. Design of a new class of agonists and receptor map of the agonist recognition site.
Year : 1995
Volume : 38
Issue : 13
First Page : 2326
Last Page : 2330
Authors : Buchheit KH, Gamse R, Giger R, Hoyer D, Klein F, Klöppner E, Pfannkuche HJ, Mattes H.
Abstract : The design and synthesis of a new class of potent and selective 5-HT4 receptor agonists containing an indole nucleus linked to a carbazimidamide are presented. A conformational study of the 5-HT4 receptor agonists serotonin and zacopride led to the identification of an initial pharmacophore and to the definition of a three-dimensional map of the 5-HT4 agonist recognition site. 1, a representative member of our new class of 5-HT4 receptor agonists, incorporates all reference structural features and matched perfectly with these models. 1 is a highly potent, full agonist at 5-HT4 receptors present in the isolated electrically stimulated guinea pig ileum preparation, with a pD2 value of 8.8, displaying selectivity (ranging from 40- to over 10,000-fold) versus other members of the serotonin receptor family.
|
The ability to inhibit [3H]prazosin binding to Alpha-1 adrenergic receptor in rat whole brain
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : SC-53116: the first selective agonist at the newly identified serotonin 5-HT4 receptor subtype.
Year : 1992
Volume : 35
Issue : 8
First Page : 1486
Last Page : 1489
Authors : Flynn DL, Zabrowski DL, Becker DP, Nosal R, Villamil CI, Gullikson GW, Moummi C, Yang DC.
|
Inhibitory activity against Alpha-1 adrenergic receptor by 3H ligand binding experiments.
|
None
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel benzamides as selective and potent gastrokinetic agents. 2. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl] benzamide citrate (AS-4370) and related compounds.
Year : 1991
Volume : 34
Issue : 2
First Page : 616
Last Page : 624
Authors : Kato S, Morie T, Kon T, Yoshida N, Karasawa T, Matsumoto J.
Abstract : The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.
|
Inhibitory activity against dopamine receptor D2 by 3H ligand binding experiments.
|
None
|
390.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel benzamides as selective and potent gastrokinetic agents. 2. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl] benzamide citrate (AS-4370) and related compounds.
Year : 1991
Volume : 34
Issue : 2
First Page : 616
Last Page : 624
Authors : Kato S, Morie T, Kon T, Yoshida N, Karasawa T, Matsumoto J.
Abstract : The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.
|
Displacement of [3H]spiroperidol from D2 dopamine receptor
|
Rattus norvegicus
|
680.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives with 5-HT3 antagonist and 5-HT4 agonist properties.
Year : 1994
Volume : 37
Issue : 9
First Page : 1320
Last Page : 1325
Authors : Monge A, Peña MC, Palop JA, Calderó JM, Roca J, García E, Romero G, del Río J, Lasheras B.
Abstract : New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2e and 2f, were more potent than ondansetron in this regard. However, these two compounds were much weaker than the typical 5-HT3 receptor antagonist as displacers of [3H]BRL-43694 binding to rat cerebral cortex homogenates or as antagonists of the bradycardia response to 5-HT in the anaesthetized rat. Like the prokinetic agent cisapride, some of the new compounds enhanced gastric emptying in rats. Compound 2f not only markedly enhanced gastric emptying but was also a potent agonist at the isolated rat oesophageal tunica muscularis mucosae, a preparation sensitive to 5-HT4 receptor stimulation, and enhanced the twitch response in the LMMP preparation. The latter effect was blocked by a high concentration of tropisetron or by previous desensitization with 5-methoxytryptamine. Compound 2f appears to show a promising pharmacological profile as a potential gastrokinetic agent.
|
Affinity towards Dopamine receptor D2 in rat striatum using [3H]spiperone as radioligand
|
Rattus norvegicus
|
227.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity.
Year : 2003
Volume : 46
Issue : 5
First Page : 702
Last Page : 715
Authors : Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S.
Abstract : A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
|
The ability to inhibit [3H]domperidone binding to dopamine receptor D2 in rat striata
|
None
|
227.0
nM
|
|
Journal : J. Med. Chem.
Title : SC-53116: the first selective agonist at the newly identified serotonin 5-HT4 receptor subtype.
Year : 1992
Volume : 35
Issue : 8
First Page : 1486
Last Page : 1489
Authors : Flynn DL, Zabrowski DL, Becker DP, Nosal R, Villamil CI, Gullikson GW, Moummi C, Yang DC.
|
The compound was evaluated for the percentage inhibition in guinea pig ileum stimulated with 10 uM 5-HT and tested at fixed concentration of 10 uM
|
Cavia porcellus
|
98.1
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives with 5-HT3 antagonist and 5-HT4 agonist properties.
Year : 1994
Volume : 37
Issue : 9
First Page : 1320
Last Page : 1325
Authors : Monge A, Peña MC, Palop JA, Calderó JM, Roca J, García E, Romero G, del Río J, Lasheras B.
Abstract : New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2e and 2f, were more potent than ondansetron in this regard. However, these two compounds were much weaker than the typical 5-HT3 receptor antagonist as displacers of [3H]BRL-43694 binding to rat cerebral cortex homogenates or as antagonists of the bradycardia response to 5-HT in the anaesthetized rat. Like the prokinetic agent cisapride, some of the new compounds enhanced gastric emptying in rats. Compound 2f not only markedly enhanced gastric emptying but was also a potent agonist at the isolated rat oesophageal tunica muscularis mucosae, a preparation sensitive to 5-HT4 receptor stimulation, and enhanced the twitch response in the LMMP preparation. The latter effect was blocked by a high concentration of tropisetron or by previous desensitization with 5-methoxytryptamine. Compound 2f appears to show a promising pharmacological profile as a potential gastrokinetic agent.
|
The compound was evaluated for the pA2 value that was estimated using 2-methyl-5-HT in five to seven different tissues in guinea pig ileum
|
Cavia porcellus
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives with 5-HT3 antagonist and 5-HT4 agonist properties.
Year : 1994
Volume : 37
Issue : 9
First Page : 1320
Last Page : 1325
Authors : Monge A, Peña MC, Palop JA, Calderó JM, Roca J, García E, Romero G, del Río J, Lasheras B.
Abstract : New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2e and 2f, were more potent than ondansetron in this regard. However, these two compounds were much weaker than the typical 5-HT3 receptor antagonist as displacers of [3H]BRL-43694 binding to rat cerebral cortex homogenates or as antagonists of the bradycardia response to 5-HT in the anaesthetized rat. Like the prokinetic agent cisapride, some of the new compounds enhanced gastric emptying in rats. Compound 2f not only markedly enhanced gastric emptying but was also a potent agonist at the isolated rat oesophageal tunica muscularis mucosae, a preparation sensitive to 5-HT4 receptor stimulation, and enhanced the twitch response in the LMMP preparation. The latter effect was blocked by a high concentration of tropisetron or by previous desensitization with 5-methoxytryptamine. Compound 2f appears to show a promising pharmacological profile as a potential gastrokinetic agent.
|
K+ channel blocking activity in human embryonic kidney cells expressing HERG Kv11.1
|
Homo sapiens
|
6.5
nM
|
|
Journal : J. Med. Chem.
Title : Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers.
Year : 2002
Volume : 45
Issue : 18
First Page : 3844
Last Page : 3853
Authors : Cavalli A, Poluzzi E, De Ponti F, Recanatini M.
Abstract : In this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers. The blockade of HERG K(+) channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K(+) channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect.
|
Inhibition of human Potassium channel HERG expressed in mammalian cells
|
Homo sapiens
|
39.81
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Prediction of hERG potassium channel affinity by traditional and hologram qSAR methods.
Year : 2003
Volume : 13
Issue : 16
First Page : 2773
Last Page : 2775
Authors : Keserü GM.
Abstract : Traditional and hologram QSAR (HQSAR) models were developed for the prediction of hERG potassium channel affinities. The models were validated on three different test sets including compounds with published patch-clamp IC(50) data and two subsets from the World Drug Index (compounds indicated to have ECG modifying adverse effect and drugs marked to be approved, respectively). Discriminant analysis performed on the full set of hERG data resulted in a traditional QSAR model that classified 83% of actives and 87% of inactives correctly. Analysis of our HQSAR model revealed it to be predictive in both IC(50) and discrimination studies.
|
Inhibition of K+ channel activity in CHO cells expressing HERG Kv11.1
|
Homo sapiens
|
45.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches.
Year : 2003
Volume : 13
Issue : 10
First Page : 1829
Last Page : 1835
Authors : Pearlstein RA, Vaz RJ, Kang J, Chen XL, Preobrazhenskaya M, Shchekotikhin AE, Korolev AM, Lysenkova LN, Miroshnikova OV, Hendrix J, Rampe D.
Abstract : A data set consisting of twenty-two sertindole analogues and ten structurally diverse inhibitors, spanning a wide range in potency, was analyzed using CoMSiA. A homology model of HERG was constructed from the crystal structure of the open MthK potassium channel. A complementary relationship between our CoMSiA and homology models is apparent when the long inhibitor axis is oriented parallel to the longitudinal axis of the pore, with the tail region pointed toward the selectivity filter. The key elements of the pharmacophore, the CoMSiA and the homology model are: (1) The hydrophobic feature optimally consists of an aromatic group that is capable of engaging in pi-stacking with a Phe656 side chain. Optionally, a second aromatic or hydrophobic group present in some inhibitors may contact an additional Phe656 side chain. (2) The basic nitrogen appears to undergo a pi-cation interaction with Tyr652. (3) The pore diameter (12A+), and depth of the selectivity loop relative to the intracellular opening, act as constraints on the conformation-dependent inhibitor dimensions.
|
Inhibitory activity against Potassium channel HERG
|
Homo sapiens
|
47.0
nM
|
|
Journal : J. Med. Chem.
Title : Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior.
Year : 2003
Volume : 46
Issue : 11
First Page : 2017
Last Page : 2022
Authors : Pearlstein R, Vaz R, Rampe D.
|
The compound was evaluated for the value in rat isolated esophageal tunica muscularis mucose in rat
|
Rattus norvegicus
|
58.88
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives with 5-HT3 antagonist and 5-HT4 agonist properties.
Year : 1994
Volume : 37
Issue : 9
First Page : 1320
Last Page : 1325
Authors : Monge A, Peña MC, Palop JA, Calderó JM, Roca J, García E, Romero G, del Río J, Lasheras B.
Abstract : New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2e and 2f, were more potent than ondansetron in this regard. However, these two compounds were much weaker than the typical 5-HT3 receptor antagonist as displacers of [3H]BRL-43694 binding to rat cerebral cortex homogenates or as antagonists of the bradycardia response to 5-HT in the anaesthetized rat. Like the prokinetic agent cisapride, some of the new compounds enhanced gastric emptying in rats. Compound 2f not only markedly enhanced gastric emptying but was also a potent agonist at the isolated rat oesophageal tunica muscularis mucosae, a preparation sensitive to 5-HT4 receptor stimulation, and enhanced the twitch response in the LMMP preparation. The latter effect was blocked by a high concentration of tropisetron or by previous desensitization with 5-methoxytryptamine. Compound 2f appears to show a promising pharmacological profile as a potential gastrokinetic agent.
|
Concentration required for inhibition of Dopamine receptor D2 using [3H]spiperone as the radioligand
|
None
|
227.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Azaadamantane benzamide 5-HT4 agonists: gastrointestinal prokinetic SC-54750.
Year : 2004
Volume : 14
Issue : 22
First Page : 5509
Last Page : 5512
Authors : Becker DP, Flynn DL, Shone RL, Gullikson G.
Abstract : Azaadamantanone 1 was converted to a series of aminoazaadamantane benzamides 9a-d, which were profiled for serotonin receptor activity. Aminomethylazaadamantane SC-54750 is a potent 5-HT(4) agonist and 5-HT(3) antagonist with in vivo efficacy in gastroparesis models and also inhibits cisplatin-induced emesis.
|
Concentration required for inhibition of alpha-1 adrenergic receptor using [3H]prazosin as the radioligand
|
None
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Azaadamantane benzamide 5-HT4 agonists: gastrointestinal prokinetic SC-54750.
Year : 2004
Volume : 14
Issue : 22
First Page : 5509
Last Page : 5512
Authors : Becker DP, Flynn DL, Shone RL, Gullikson G.
Abstract : Azaadamantanone 1 was converted to a series of aminoazaadamantane benzamides 9a-d, which were profiled for serotonin receptor activity. Aminomethylazaadamantane SC-54750 is a potent 5-HT(4) agonist and 5-HT(3) antagonist with in vivo efficacy in gastroparesis models and also inhibits cisplatin-induced emesis.
|
Concentration required for inhibition of 5-hydroxytryptamine 3 receptor using [3H]GR-65630 as the radioligand
|
None
|
134.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Azaadamantane benzamide 5-HT4 agonists: gastrointestinal prokinetic SC-54750.
Year : 2004
Volume : 14
Issue : 22
First Page : 5509
Last Page : 5512
Authors : Becker DP, Flynn DL, Shone RL, Gullikson G.
Abstract : Azaadamantanone 1 was converted to a series of aminoazaadamantane benzamides 9a-d, which were profiled for serotonin receptor activity. Aminomethylazaadamantane SC-54750 is a potent 5-HT(4) agonist and 5-HT(3) antagonist with in vivo efficacy in gastroparesis models and also inhibits cisplatin-induced emesis.
|
Concentration required for inhibition of 5-hydroxytryptamine 2 receptor using [3H]ketanserin as the radioligand
|
None
|
6.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Azaadamantane benzamide 5-HT4 agonists: gastrointestinal prokinetic SC-54750.
Year : 2004
Volume : 14
Issue : 22
First Page : 5509
Last Page : 5512
Authors : Becker DP, Flynn DL, Shone RL, Gullikson G.
Abstract : Azaadamantanone 1 was converted to a series of aminoazaadamantane benzamides 9a-d, which were profiled for serotonin receptor activity. Aminomethylazaadamantane SC-54750 is a potent 5-HT(4) agonist and 5-HT(3) antagonist with in vivo efficacy in gastroparesis models and also inhibits cisplatin-induced emesis.
|
Inhibitory concentration against potassium channel HERG
|
None
|
39.81
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A discriminant model constructed by the support vector machine method for HERG potassium channel inhibitors.
Year : 2005
Volume : 15
Issue : 11
First Page : 2886
Last Page : 2890
Authors : Tobita M, Nishikawa T, Nagashima R.
Abstract : HERG attracts attention as a risk factor for arrhythmia, which might trigger torsade de pointes. A highly accurate classifier of chemical compounds for inhibition of the HERG potassium channel is constructed using support vector machine. For two test sets, our discriminant models achieved 90% and 95% accuracy, respectively. The classifier is even applied for the prediction of cardio vascular adverse effects to achieve about 70% accuracy. While modest inhibitors are partly characterized by properties linked to global structure of a molecule including hydrophobicity and diameter, strong inhibitors are exclusively characterized by properties linked to substructures of a molecule.
|
Inhibition of partially open human voltage-gated potassium channel subunit Kv11.1 (ERG K+ channel)
|
Homo sapiens
|
6.457
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A two-state homology model of the hERG K+ channel: application to ligand binding.
Year : 2005
Volume : 15
Issue : 6
First Page : 1737
Last Page : 1741
Authors : Rajamani R, Tounge BA, Li J, Reynolds CH.
Abstract : Homology models based on available K+ channel structures have been used to construct a multiple state representation of the hERG cardiac K+ channel. These states are used to capture the flexibility of the channel. We show that this flexibility is essential in order to correctly model the binding affinity of a set of diverse ligands. Using this multiple state approach, a binding affinity model was constructed for set of known hERG channel binders. The predicted pIC50s are in good agreement with experiment (RMSD: 0.56 kcal/mol). In addition, these calculations provide structures for the bound ligands that are consistent with published mutation studies. These computed ligand bound complex structures can be used to guide synthesis of analogs with reduced hERG liability.
|
Displacement of [3H]GR65630 from 5HT3 receptor in brain cortex from Wistar rat
|
Rattus norvegicus
|
134.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists.
Year : 2006
Volume : 49
Issue : 3
First Page : 1125
Last Page : 1139
Authors : Becker DP, Flynn DL, Moormann AE, Nosal R, Villamil CI, Loeffler R, Gullikson GW, Moummi C, Yang DC.
Abstract : A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors.
|
Displacement of [3H]GR-113808 from 5HT4 receptor in guinea pig striatum
|
Cavia porcellus
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists.
Year : 2006
Volume : 49
Issue : 3
First Page : 1125
Last Page : 1139
Authors : Becker DP, Flynn DL, Moormann AE, Nosal R, Villamil CI, Loeffler R, Gullikson GW, Moummi C, Yang DC.
Abstract : A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors.
|
Agonism at 5HT4 receptor in rat tunica muscularis mucosa
|
Rattus norvegicus
|
54.7
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists.
Year : 2006
Volume : 49
Issue : 3
First Page : 1125
Last Page : 1139
Authors : Becker DP, Flynn DL, Moormann AE, Nosal R, Villamil CI, Loeffler R, Gullikson GW, Moummi C, Yang DC.
Abstract : A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors.
|
Binding affinity to 5HT2 receptor
|
None
|
6.1
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists.
Year : 2006
Volume : 49
Issue : 3
First Page : 1125
Last Page : 1139
Authors : Becker DP, Flynn DL, Moormann AE, Nosal R, Villamil CI, Loeffler R, Gullikson GW, Moummi C, Yang DC.
Abstract : A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors.
|
Binding affinity to dopamine receptor D2
|
Homo sapiens
|
227.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists.
Year : 2006
Volume : 49
Issue : 3
First Page : 1125
Last Page : 1139
Authors : Becker DP, Flynn DL, Moormann AE, Nosal R, Villamil CI, Loeffler R, Gullikson GW, Moummi C, Yang DC.
Abstract : A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors.
|
Binding affinity to adrenergic alpha-1 receptor
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists.
Year : 2006
Volume : 49
Issue : 3
First Page : 1125
Last Page : 1139
Authors : Becker DP, Flynn DL, Moormann AE, Nosal R, Villamil CI, Loeffler R, Gullikson GW, Moummi C, Yang DC.
Abstract : A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors.
|
Cardiotoxicity in iv dosed Dunkin-Hartley guinea pig assessed as drug level required to evoke 50 ms QTc prolongation administered as 3 fold cumulative doses measured every 10 seconds at end of every 20 mins follow up period of individual dose by ECG
|
Cavia porcellus
|
2.12
umol/Kg
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of "toxicophoric" features for predicting drug-induced QT interval prolongation.
Year : 2008
Volume : 43
Issue : 11
First Page : 2479
Last Page : 2488
Authors : Coi A, Massarelli I, Testai L, Calderone V, Bianucci AM.
Abstract : Drugs delaying cardiac repolarization by blockade of hERG K(+) channel generally prolong the QT interval of the electrocardiogram, an effect regarded as a cardiac risk factor with the potential to cause 'torsade des pointes'-type arrhythmias in humans. The present study applied a homology building technique and molecular dynamics simulations to model the pore of hERG K(+) channel. A docking analysis was then performed on selected ligands which were classified as QT-prolonging or non-prolonging after experimental measurements in in vivo anesthetized guinea pig. The results of this structural analysis provided a "toxicophoric" model that was further exploited to inspect a dataset of known QT-prolonging/non-prolonging molecules. The emerging major chemical features to be avoided, in order to obtain cardiac safe therapeutic agents, comprise the simultaneous presence of (i) a protonated nitrogen atom within an observed range of distances from a heteroatom; (ii) aromatic groups capable of interacting within an area defined by Gly657 residues of the pore or within an area located at the top of the longitudinal axis of the pore. Moreover, additional hydrophobic moieties interacting with one of the equatorial cavities located in the area near-by Tyr652 residues and/or with a hydrophobic ring defined by Phe656 residues should be avoided.
|
Inhibition of wild-type human ERG expressed in HEK293 cells by whole cell patch clamp method
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Docking model of drug binding to the human ether-à-go-go potassium channel guided by tandem dimer mutant patch-clamp data: a synergic approach.
Year : 2009
Volume : 52
Issue : 6
First Page : 1630
Last Page : 1638
Authors : Imai YN, Ryu S, Oiki S.
Abstract : To characterize drug binding to the human ether-a-go-go related gene (hERG) channel, a synergic approach interplaying patch-clamp experiments and a docking study was developed. Mutations were introduced into concatenated dimers of the hERG channel that were assembled into a heterotetramer with mutated diagonal subunits. The binding affinities of three drugs (cisapride, terfenadine, and N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide dihydrochloride (E-4031, 1)) to a set of mutant channels were examined electrophysiologically to assess the involved residues, their number, and relative positions. Cisapride and 1 interacted with Tyr652 residues on adjacent subunits, while terfenadine interacted with Tyr652 residues on diagonal, but not on adjacent, subunits. Phe656 was involved in the binding of all three drugs, and Ser624 was found to be only involved in cisapride and 1. The docking models demonstrated that pi-pi and CH-pi interactions rather than cation-pi interaction play a key role in drug binding to the hERG channel.
|
Inhibition of human ERG td[wt:Y652A] mutant expressed in HEK293 cells by whole cell patch clamp method
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Docking model of drug binding to the human ether-à-go-go potassium channel guided by tandem dimer mutant patch-clamp data: a synergic approach.
Year : 2009
Volume : 52
Issue : 6
First Page : 1630
Last Page : 1638
Authors : Imai YN, Ryu S, Oiki S.
Abstract : To characterize drug binding to the human ether-a-go-go related gene (hERG) channel, a synergic approach interplaying patch-clamp experiments and a docking study was developed. Mutations were introduced into concatenated dimers of the hERG channel that were assembled into a heterotetramer with mutated diagonal subunits. The binding affinities of three drugs (cisapride, terfenadine, and N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide dihydrochloride (E-4031, 1)) to a set of mutant channels were examined electrophysiologically to assess the involved residues, their number, and relative positions. Cisapride and 1 interacted with Tyr652 residues on adjacent subunits, while terfenadine interacted with Tyr652 residues on diagonal, but not on adjacent, subunits. Phe656 was involved in the binding of all three drugs, and Ser624 was found to be only involved in cisapride and 1. The docking models demonstrated that pi-pi and CH-pi interactions rather than cation-pi interaction play a key role in drug binding to the hERG channel.
|
Inhibition of human ERG td[wt:F656A] mutant expressed in HEK293 cells by whole cell patch clamp method
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Docking model of drug binding to the human ether-à-go-go potassium channel guided by tandem dimer mutant patch-clamp data: a synergic approach.
Year : 2009
Volume : 52
Issue : 6
First Page : 1630
Last Page : 1638
Authors : Imai YN, Ryu S, Oiki S.
Abstract : To characterize drug binding to the human ether-a-go-go related gene (hERG) channel, a synergic approach interplaying patch-clamp experiments and a docking study was developed. Mutations were introduced into concatenated dimers of the hERG channel that were assembled into a heterotetramer with mutated diagonal subunits. The binding affinities of three drugs (cisapride, terfenadine, and N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide dihydrochloride (E-4031, 1)) to a set of mutant channels were examined electrophysiologically to assess the involved residues, their number, and relative positions. Cisapride and 1 interacted with Tyr652 residues on adjacent subunits, while terfenadine interacted with Tyr652 residues on diagonal, but not on adjacent, subunits. Phe656 was involved in the binding of all three drugs, and Ser624 was found to be only involved in cisapride and 1. The docking models demonstrated that pi-pi and CH-pi interactions rather than cation-pi interaction play a key role in drug binding to the hERG channel.
|
Inhibition of human ERG S624A mutant expressed in HEK293 cells by whole cell patch clamp method
|
Homo sapiens
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Docking model of drug binding to the human ether-à-go-go potassium channel guided by tandem dimer mutant patch-clamp data: a synergic approach.
Year : 2009
Volume : 52
Issue : 6
First Page : 1630
Last Page : 1638
Authors : Imai YN, Ryu S, Oiki S.
Abstract : To characterize drug binding to the human ether-a-go-go related gene (hERG) channel, a synergic approach interplaying patch-clamp experiments and a docking study was developed. Mutations were introduced into concatenated dimers of the hERG channel that were assembled into a heterotetramer with mutated diagonal subunits. The binding affinities of three drugs (cisapride, terfenadine, and N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide dihydrochloride (E-4031, 1)) to a set of mutant channels were examined electrophysiologically to assess the involved residues, their number, and relative positions. Cisapride and 1 interacted with Tyr652 residues on adjacent subunits, while terfenadine interacted with Tyr652 residues on diagonal, but not on adjacent, subunits. Phe656 was involved in the binding of all three drugs, and Ser624 was found to be only involved in cisapride and 1. The docking models demonstrated that pi-pi and CH-pi interactions rather than cation-pi interaction play a key role in drug binding to the hERG channel.
|
Inhibition of human ERG channel
|
Homo sapiens
|
6.7
nM
|
|
Inhibition of human ERG channel
|
Homo sapiens
|
6.7
nM
|
|
Journal : J. Med. Chem.
Title : Side chain flexibilities in the human ether-a-go-go related gene potassium channel (hERG) together with matched-pair binding studies suggest a new binding mode for channel blockers.
Year : 2009
Volume : 52
Issue : 14
First Page : 4266
Last Page : 4276
Authors : Zachariae U, Giordanetto F, Leach AG.
Abstract : The cardiac hERG K(+) channel constitutes a long-standing and expensive antitarget for the drug industry. From a study of the flexibility of hERG around its internal binding cavity, we have developed a new structural model of drug binding to hERG, which involves binding orthogonal to the pore channel and therefore can exploit the up to 4-fold symmetry of the tetrameric channel. This binding site has a base formed by four tyrosine side chains that complement reported ligand-based pharmacophores. The model is able to rationalize reduced hERG potency in matched molecular pair studies and suggests design guidelines to optimize against hERG not relying simply on lipophilicity reduction. The binding model also suggests a molecular mechanism for the link between high-affinity hERG binding and C-type inactivation.
|
Inhibition of human ERG expressed in CHO cells by whole cell patch clamp technique
|
Homo sapiens
|
39.81
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Support vector machines classification of hERG liabilities based on atom types.
Year : 2008
Volume : 16
Issue : 11
First Page : 6252
Last Page : 6260
Authors : Jia L, Sun H.
Abstract : Drug-induced long QT syndrome (LQTS) can cause critical cardiovascular side effects and has accounted for the withdrawal of several drugs from the market. Blockade of the potassium ion channel encoded by the human ether-a-go-go-related gene (hERG) has been identified as a major contributor to drug-induced LQTS. Experimental measurement of hERG activity for each compound in development is costly and time-consuming, thus it is beneficial to develop a predictive hERG model. Here, we present a hERG classification model formulated using support vector machines (SVM) as machine learning method and using atom types as molecular descriptors. The training set used in this study was composed of 977 corporate compounds with hERG activities measured under the same conditions. The impact of soft margin and kernel function on the performance of the SVM models was examined. The robustness of SVM was evaluated by comparing the predictive power of the models built with 90%, 50%, and 10% of the training set data. The final SVM model was able to correctly classify 94% of an external testing set containing 66 drug molecules. The most important atom types with respect to discriminative power were extracted and analyzed.
|
Inhibition of human ERG in MCF7 cells
|
Homo sapiens
|
6.457
nM
|
|
Journal : Eur. J. Med. Chem.
Title : GRIND-based 3D-QSAR and CoMFA to investigate topics dominated by hydrophobic interactions: the case of hERG K+ channel blockers.
Year : 2009
Volume : 44
Issue : 5
First Page : 1926
Last Page : 1932
Authors : Ermondi G, Visentin S, Caron G.
Abstract : The study compares GRIND-based 3D-QSAR and CoMFA [A. Cavalli, E. Poluzzi, F. De Ponti, M. Recanatini, J. Med. Chem, 45(2002), 3844-53] to investigate a biological topic dominated by hydrophobic interactions, e.g. hERG K(+) channel blocking activity. As expected, models are found by both methods and there is a fine agreement between statistical and graphical results as well. However, a closer inspection revealed that failures in the prediction of hERG blocking activity for lipophilic compounds were registered for both methods. The study explores the reasons for these failures which are strongly dependent on the chosen method, and gives some suggestions to handle with these topics.
|
Inhibition of CETP in rabbit serum at 10 uM after 1 hr by fluorescent cholesteryl esters transfer assay
|
Oryctolagus cuniculus
|
10.6
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration.
Year : 2010
Volume : 45
Issue : 4
First Page : 1598
Last Page : 1617
Authors : Abu Khalaf R, Abu Sheikha G, Bustanji Y, Taha MO.
Abstract : Cholesteryl ester transfer protein (CETP) is involved in trafficking lipoprotein particles and neutral lipids between HDL and LDL and therefore is considered a valid target for treating dyslipidemic conditions and complications. Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements for potent CETP inhibitors. Two pharmacophores emerged in the optimal QSAR equation (r(2)=0.800, n=96, F=72.1, r(2)(LOO) =0.775, r(2)(PRESS) against 22 external test inhibitors=0.707) suggesting the existence of at least two distinct binding modes accessible to ligands within CETP binding pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic (ROC) curve profiles. The validity of our modeling approach was experimentally established by the identification of several CETP inhibitory leads retrieved via in silico screening of the National Cancer Institute (NCI) list of compounds and an in house built database of drugs and agrochemicals. Two hits illustrated low micromolar IC(50) values: NSC 40331 (IC(50)=6.5 microM) and NSC 89508 (IC(50)=1.9 microM). Active hits were then used to guide synthetic exploration of a new series of CETP inhibitors.
|
Inhibition of human ERG
|
Homo sapiens
|
6.761
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: Potassium Channel HERG radioligand binding (ligand: [3H] Astemizole)
|
None
|
170.1
nM
|
|
DRUGMATRIX: Potassium Channel HERG radioligand binding (ligand: [3H] Astemizole)
|
None
|
139.4
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
|
3.856
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2A radioligand binding (ligand: [3H] Ketanserin)
|
None
|
1.102
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
|
120.0
nM
|
|
DRUGMATRIX: Alpha-1A adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
49.0
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-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
16.0
nM
|
|
DRUGMATRIX: Alpha-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
8.654
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
|
189.0
nM
|
|
DRUGMATRIX: Alpha-1D adrenergic receptor radioligand binding (ligand: prazosin)
|
None
|
93.0
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
|
666.0
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-2B adrenergic receptor radioligand binding (ligand: Rauwolscine)
|
None
|
524.0
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
|
780.0
nM
|
|
DRUGMATRIX: Adrenergic Alpha-2C radioligand binding (ligand: [3H] MK-912)
|
None
|
113.0
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
|
802.0
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Benzothiazepine radioligand binding (ligand: [3H] Diltiazem)
|
Rattus norvegicus
|
713.0
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
|
110.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2B radioligand binding (ligand: [3H] Lysergic acid diethylamide)
|
None
|
70.0
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
|
767.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2C radioligand binding (ligand: [3H] Mesulergine)
|
None
|
402.0
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
|
273.0
nM
|
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT4 radioligand binding (ligand: [3H] GR-113808)
|
Cavia porcellus
|
45.0
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: Transporter, Serotonin (5-Hydroxytryptamine) (SERT) radioligand binding (ligand: [3H] Paroxetine)
|
None
|
384.0
nM
|
|
DRUGMATRIX: Transporter, Serotonin (5-Hydroxytryptamine) (SERT) radioligand binding (ligand: [3H] Paroxetine)
|
None
|
204.0
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
|
994.0
nM
|
|
DRUGMATRIX: Sigma1 radioligand binding (ligand: [3H] Haloperidol)
|
None
|
418.0
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
|
177.0
nM
|
|
DRUGMATRIX: Sigma2 radioligand binding (ligand: [3H] Ifenprodil)
|
Rattus norvegicus
|
109.0
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
|
530.0
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Phenylalkylamine radioligand binding (ligand: [3H] (-)-Desmethoxyverapamil (D-888))
|
Rattus norvegicus
|
515.0
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: CYP450, 2D6 enzyme inhibition (substrate: 3-Cyano-7-ethoxycoumarin)
|
None
|
70.0
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: CYP450, 3A4 enzyme inhibition (substrate: 7-Benzyloxy-4-(trifluoromethyl)-coumarin)
|
None
|
300.0
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
|
473.0
nM
|
|
DRUGMATRIX: Dopamine D2L radioligand binding (ligand: [3H] Spiperone)
|
None
|
158.0
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
|
144.0
nM
|
|
DRUGMATRIX: Dopamine D3 radioligand binding (ligand: [3H] Spiperone)
|
None
|
49.0
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 ERG at 10 uM
|
Homo sapiens
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery and pharmacological profile of new 1H-indazole-3-carboxamide and 2H-pyrrolo[3,4-c]quinoline derivatives as selective serotonin 4 receptor ligands.
Year : 2012
Volume : 55
Issue : 22
First Page : 9446
Last Page : 9466
Authors : Furlotti G, Alisi MA, Apicella C, Capezzone de Joannon A, Cazzolla N, Costi R, Cuzzucoli Crucitti G, Garrone B, Iacovo A, Magarò G, Mangano G, Miele G, Ombrato R, Pescatori L, Polenzani L, Rosi F, Vitiello M, Di Santo R.
Abstract : Since the discovery of the serotonin 4 receptor (5-HT(4)R), a large number of receptor ligands have been studied. The safety concerns and the lack of market success of these ligands have mainly been attributed to their lack of selectivity. In this study we describe the discovery of N-[(4-piperidinyl)methyl]-1H-indazole-3-carboxamide and 4-[(4-piperidinyl)methoxy]-2H-pyrrolo[3,4-c]quinoline derivatives as new 5-HT(4)R ligands endowed with high selectivity over the serotonin 2A receptor and human ether-a-go-go-related gene potassium ion channel. Within these series, two molecules (11 ab and 12 g) were identified as potent and selective 5-HT(4)R antagonists with good in vitro pharmacokinetic properties. These compounds were evaluated for their antinociceptive action in two analgesia animal models. 12 g showed a significant antinociceptive effect in both models and is proposed as an interesting lead compound as a 5-HT(4)R antagonist with analgesic action.
|
Inhibition of human ERG at 1 uM by cell-based electrophysiology assay
|
Homo sapiens
|
96.0
%
|
|
Journal : J. Med. Chem.
Title : Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia.
Year : 2012
Volume : 55
Issue : 20
First Page : 8721
Last Page : 8734
Authors : Bavetsias V, Crumpler S, Sun C, Avery S, Atrash B, Faisal A, Moore AS, Kosmopoulou M, Brown N, Sheldrake PW, Bush K, Henley A, Box G, Valenti M, de Haven Brandon A, Raynaud FI, Workman P, Eccles SA, Bayliss R, Linardopoulos S, Blagg J.
Abstract : Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20-35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4-11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children.
|
Binding affinity to human serotonin 5-HT2B receptor
|
Homo sapiens
|
39.81
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.
Year : 2013
Volume : 23
Issue : 14
First Page : 4210
Last Page : 4215
Authors : McKinnell RM, Armstrong SR, Beattie DT, Fatheree PR, Long DD, Marquess DG, Shaw JP, Vickery RG.
Abstract : The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
|
Binding affinity to human serotonin 5-HT1A receptor
|
Homo sapiens
|
794.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.
Year : 2013
Volume : 23
Issue : 14
First Page : 4210
Last Page : 4215
Authors : McKinnell RM, Armstrong SR, Beattie DT, Fatheree PR, Long DD, Marquess DG, Shaw JP, Vickery RG.
Abstract : The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
|
Binding affinity to human serotonin 5-HT2A receptor
|
Homo sapiens
|
6.31
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.
Year : 2013
Volume : 23
Issue : 14
First Page : 4210
Last Page : 4215
Authors : McKinnell RM, Armstrong SR, Beattie DT, Fatheree PR, Long DD, Marquess DG, Shaw JP, Vickery RG.
Abstract : The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
|
Induction of 5-HT4 receptor-mediated contraction in guinea pig longitudinal muscle myenteric plexus
|
Cavia porcellus
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.
Year : 2013
Volume : 23
Issue : 14
First Page : 4210
Last Page : 4215
Authors : McKinnell RM, Armstrong SR, Beattie DT, Fatheree PR, Long DD, Marquess DG, Shaw JP, Vickery RG.
Abstract : The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
|
Binding affinity to serotonin 5-HT4 receptor (unknown origin)
|
Homo sapiens
|
125.89
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.
Year : 2013
Volume : 23
Issue : 14
First Page : 4210
Last Page : 4215
Authors : McKinnell RM, Armstrong SR, Beattie DT, Fatheree PR, Long DD, Marquess DG, Shaw JP, Vickery RG.
Abstract : The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
|
Inhibition of human ERG channel at 3 uM
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.
Year : 2013
Volume : 23
Issue : 14
First Page : 4210
Last Page : 4215
Authors : McKinnell RM, Armstrong SR, Beattie DT, Fatheree PR, Long DD, Marquess DG, Shaw JP, Vickery RG.
Abstract : The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
|
Agonist activity at human recombinant 5HT4 receptor assessed as cAMP accumulation
|
Homo sapiens
|
79.43
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.
Year : 2013
Volume : 23
Issue : 14
First Page : 4210
Last Page : 4215
Authors : McKinnell RM, Armstrong SR, Beattie DT, Fatheree PR, Long DD, Marquess DG, Shaw JP, Vickery RG.
Abstract : The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
|
Binding affinity to human recombinant 5HT4 receptor
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.
Year : 2013
Volume : 23
Issue : 14
First Page : 4210
Last Page : 4215
Authors : McKinnell RM, Armstrong SR, Beattie DT, Fatheree PR, Long DD, Marquess DG, Shaw JP, Vickery RG.
Abstract : The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
|
Inhibition of human ERG expressed in HEK293 cells assessed as membrane depolarization at 100 nM by patch-clamp method
|
Homo sapiens
|
89.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers.
Year : 2013
Volume : 21
Issue : 19
First Page : 5936
Last Page : 5944
Authors : Tang L, Zhao L, Hong L, Yang F, Sheng R, Chen J, Shi Y, Zhou N, Hu Y.
Abstract : A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer's disease therapy. Most of these synthesized compounds exhibited moderate to potent antagonistic activities in CREs driven luciferase assay. In particular, compound 2d demonstrated the most favorable H3 receptor antagonistic activity with the IC50 value of 0.049μM. Besides, it also displayed high binding affinity to H3 receptor (Ki=4.26±2.55nM) and high selectivity over other three histamine receptors. Moreover, 2d and other two 3-substituted indole derivatives 1d and 3d exerted potent ABTS radical cation scavenging capacities similar to melatonin. Above results illustrate that 2d is an interesting lead for extensive optimization to explore new drug candidate for AD therapy.
|
Inhibition of human ERG channel expressed in HEK293 cells at 0.1 uM after 3 to 5.7 mins by whole-cell patch clamp technique
|
Homo sapiens
|
83.6
%
|
|
Journal : J. Med. Chem.
Title : Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent.
Year : 2014
Volume : 57
Issue : 10
First Page : 4213
Last Page : 4238
Authors : Jin CH, Krishnaiah M, Sreenu D, Subrahmanyam VB, Rao KS, Lee HJ, Park SJ, Park HJ, Lee K, Sheen YY, Kim DK.
Abstract : A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-β type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a]pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC50 value of 0.013 μM in a kinase assay and with IC50 values of 0.0165 and 0.0121 μM in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor. Pharmacokinetic study with 12b·HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng × h/mL and maximum plasma concentration (Cmax) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b.
|
Inhibition of human ERG expressed in CHO cells by whole-cell patch clamp assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and structure-activity relationship studies of novel fused heterocycles-linked triazoles with good activity and water solubility.
Year : 2014
Volume : 57
Issue : 9
First Page : 3687
Last Page : 3706
Authors : Cao X, Sun Z, Cao Y, Wang R, Cai T, Chu W, Hu W, Yang Y.
Abstract : Triazoles with fused-heterocycle nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SAR of antifungal triazoles. Tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine and tetrahydro-thiazolo[5,4-c]pyridine nuclei were preferable to the other four fused-heterocycle nuclei investigated. Potent in vitro activity, broad spectrum and better water solubility were attained when triazoles containing nitrogen aromatic heterocycles were attached to these two nuclei. The most potent compounds 27aa and 45x, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against Candida, Cryptococcus, and Aspergillus spp., as well as selected fluconazole-resistant strains. A high water-soluble compound 58 (the disulfate salt of 45x) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with 27aa displayed significantly improved survival rates. 27aa also showed favorable pharmacokinetic (PK) profiles.
|
Displacement of [3H]GR113808 from Dunkin-Hartley guinea pig brain striatum 5HT4R after 30 mins
|
Cavia porcellus
|
20.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and structure-activity relationship studies in serotonin 5-HT4 receptor ligands based on a benzo[de][2,6]naphthridine scaffold.
Year : 2014
Volume : 82
First Page : 36
Last Page : 46
Authors : Castriconi F, Paolino M, Giuliani G, Anzini M, Campiani G, Mennuni L, Sabatini C, Lanza M, Caselli G, De Rienzo F, Menziani MC, Sbraccia M, Molinari P, Costa T, Cappelli A.
Abstract : A small series of serotonin 5-HT4 receptor ligands has been designed from flexible 2-methoxyquinoline compounds 7a,b by applying the conformational constraint approach. Ligands 7a,b and the corresponding conformationally constrained analogues 8a-g were synthesized and their interactions with the 5-HT4 receptor were examined by measuring both binding affinity and the ability to promote or inhibit receptor-G protein coupling. Ester derivative 7a and conformationally constrained compound 8b were demonstrated to be the most interesting compounds showing a nanomolar 5-HT4R affinity similar to that shown by reference ligands cisapride (1) and RS-23,597-190 (4). The result was rationalized by docking studies in term of high similarity in the binding modalities of flexible 7a and conformationally constrained 8b. The intrinsic efficacy of some selected ligands was determined by evaluating the receptor-G protein coupling and the results obtained demonstrated that the nature and the position of substituents play a critical role in the interaction of these ligands with their receptor.
|
Inhibition of human ERG assessed as reduction in channel currents at 1 uM
|
Homo sapiens
|
92.4
%
|
|
Journal : J. Med. Chem.
Title : A chemical tuned strategy to develop novel irreversible EGFR-TK inhibitors with improved safety and pharmacokinetic profiles.
Year : 2014
Volume : 57
Issue : 23
First Page : 9889
Last Page : 9900
Authors : Xia G, Chen W, Zhang J, Shao J, Zhang Y, Huang W, Zhang L, Qi W, Sun X, Li B, Xiang Z, Ma C, Xu J, Deng H, Li Y, Li P, Miao H, Han J, Liu Y, Shen J, Yu Y.
Abstract : Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFR(WT), EGFR(T790M) as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of 5a at a dose of 30 mg/kg induced tumor regression in a murine-EGFR(L858R/T790M) driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance.
|
Inhibition of human ERG assessed as reduction in channel currents at 0.1 uM
|
Homo sapiens
|
65.5
%
|
|
Journal : J. Med. Chem.
Title : A chemical tuned strategy to develop novel irreversible EGFR-TK inhibitors with improved safety and pharmacokinetic profiles.
Year : 2014
Volume : 57
Issue : 23
First Page : 9889
Last Page : 9900
Authors : Xia G, Chen W, Zhang J, Shao J, Zhang Y, Huang W, Zhang L, Qi W, Sun X, Li B, Xiang Z, Ma C, Xu J, Deng H, Li Y, Li P, Miao H, Han J, Liu Y, Shen J, Yu Y.
Abstract : Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFR(WT), EGFR(T790M) as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of 5a at a dose of 30 mg/kg induced tumor regression in a murine-EGFR(L858R/T790M) driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance.
|
Inhibition of hERG K channel
|
None
|
6.5
nM
|
|
Journal : Cardiovasc. Res.
Title : Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk.
Year : 2011
Volume : 91
First Page : 53
Last Page : 61
Authors : Mirams GR, Cui Y, Sher A, Fink M, Cooper J, Heath BM, McMahon NC, Gavaghan DJ, Noble D.
Abstract : The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC(50)) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk.We collected multiple ion channel data (hERG, Na, L-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC(50) values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers.The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.
|
Inhibition of human ERG expressed in CHO cells assessed as whole cell current by patch clamp assay
|
Homo sapiens
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and Biological Evaluation of Novel Olean-28,13β-lactams as Potential Antiprostate Cancer Agents.
Year : 2015
Volume : 58
Issue : 11
First Page : 4506
Last Page : 4520
Authors : Ai Y, Hu Y, Kang F, Lai Y, Jia Y, Huang Z, Peng S, Ji H, Tian J, Zhang Y.
Abstract : γ-Lactam is an important structural motif in a large number of biologically active natural products and synthetic small pharmaceutical molecules. However, there is currently no effective approach to construct γ-lactam ring directly from natural rigid polycyclic amides. Herein, we report a facile methodology for synthesis of a new group of olean-28,13β-lactams (10a-j) from their corresponding amides, promoted by an easily available reagent 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), through an intramolecular dehydrogenative C-N coupling reaction via a radical ion mechanism. Biological evaluation indicated that the most active lactam 10h displayed potent antiproliferative activity against human cancer cells but 13.84- to 16.92-fold less inhibitory activity on noncancer cells in vitro. In addition, 10h significantly inhibited the growth of implanted prostate cancer in vivo. Furthermore, 10h induced cell cycle arrest and apoptosis and down-regulated the AKT/mTOR signaling in DU-145 cells. Finally, 10h was more stable in rat plasma and human liver microsomes than CDDO-Me and had little hERG channel inhibitory activity. Collectively, 10h may be a potential antiprostate cancer agent for further investigation.
|
Inhibition of human ERG overexpressed in CHO cells at 3 uM by Qpatch method relative to control
|
Homo sapiens
|
98.67
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of isoquinoline-based derivatives as novel histone deacetylase inhibitors.
Year : 2015
Volume : 23
Issue : 17
First Page : 5881
Last Page : 5890
Authors : Yang W, Li L, Wang Y, Wu X, Li T, Yang N, Su M, Sheng L, Zheng M, Zang Y, Li J, Liu H.
Abstract : The design, synthesis and biological evaluation of a series of isoquinoline-based hydroxamic acid compounds as novel HDACs inhibitors were reported herein. A detailed SAR study showed most of the compounds displayed good to excellent inhibitory activities against HDAC1, 3, 6. The IC50 values of compound 10 c against HDAC1, 3, 6 were 4.17 ± 0.11 nM, 4.00 ± 0.10 nM, 3.77 ± 0.07 nM, respectively. Most of the compounds showed great anti-proliferative activities against RPMI 8226, HCT 116 and Hep G2 cells. The IC50 values of compounds 10 a-h against RPMI 8226 cancer cell proliferation were all below 1 μM. HCT 116 cell was sensitive to the compounds 10 a, 10 f-g and 18 a with the IC50 values <0.3 μM. The active compounds 10a-d did not show inhibitory activity against hERG channel. All these evidence indicated these compounds had great potential as HDACs inhibitors for the further development.
|
Inhibition of human ERG overexpressed in CHO cells by Qpatch method
|
Homo sapiens
|
98.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of isoquinoline-based derivatives as novel histone deacetylase inhibitors.
Year : 2015
Volume : 23
Issue : 17
First Page : 5881
Last Page : 5890
Authors : Yang W, Li L, Wang Y, Wu X, Li T, Yang N, Su M, Sheng L, Zheng M, Zang Y, Li J, Liu H.
Abstract : The design, synthesis and biological evaluation of a series of isoquinoline-based hydroxamic acid compounds as novel HDACs inhibitors were reported herein. A detailed SAR study showed most of the compounds displayed good to excellent inhibitory activities against HDAC1, 3, 6. The IC50 values of compound 10 c against HDAC1, 3, 6 were 4.17 ± 0.11 nM, 4.00 ± 0.10 nM, 3.77 ± 0.07 nM, respectively. Most of the compounds showed great anti-proliferative activities against RPMI 8226, HCT 116 and Hep G2 cells. The IC50 values of compounds 10 a-h against RPMI 8226 cancer cell proliferation were all below 1 μM. HCT 116 cell was sensitive to the compounds 10 a, 10 f-g and 18 a with the IC50 values <0.3 μM. The active compounds 10a-d did not show inhibitory activity against hERG channel. All these evidence indicated these compounds had great potential as HDACs inhibitors for the further development.
|
Binding Assay: The binding affinity of the compounds for a human 5-HT4 receptor was assayed according to the method as disclosed in the literature [Wyngaert et al., Journal of Neurochemistry, (1997) 69, 1810-1819]. For this purpose, COS-7 cells expressing the human 5-HT4 receptor were constructed and homogenized to obtain membrane homogenates which were then used in binding assay experiments. For the binding assay, the membrane homogenates were respectively mixed and incubated with different concentrations of test materials and [H3]-GR113808 (Amersham Biosciences). The concentrations of the individual test materials were set to 4 uM, 1 uM, 0.25 uM, and 0.0625 uM, respectively, and the concentration of [H3]-GR113808 was set to 0.595 nM. After the incubation was completed, the reaction products were collected in GF/B glass fiber filters using a Packard cell harvester, and the bound radioactivity was then determined using a liquid cell scintillation counter (Packard TopCount NXT).
|
None
|
0.362
nM
|
|
Title : Benzamide derivatives
Year : 2015
|
Inhibition of human ERG expressed in CHO cells by Qpatch assay
|
Homo sapiens
|
150.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of indolin-2-one-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase3 (FLT3).
Year : 2017
Volume : 127
First Page : 72
Last Page : 86
Authors : Ma F, Liu P, Lei M, Liu J, Wang H, Zhao S, Hu L.
Abstract : Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately one third of acute myeloid leukemia (AML) patients, which has been proposed as a promising drug target for AML therapy. A series of indolin-2-one derivatives bearing different groups at the solvent interface position based on sunitinib as FLT3 inhibitors were designed, synthesized and evaluated in FLT3-dependent human AML cell line MV4-11. Structure-activity relationship (SAR)analysis showed that heterocyclic alkane at the solvent interface position could significantly increase the potency for the inhibition of proliferation of MV4-11 cell line. Compound 10a and 10d exhibited better efficacy (MV4-11, IC50: 14.7 nM for 10a and 24.8 nM for 10d) than positive control sunitinib (MV4-11, IC50: 38.5 nM). The kinase and cellular inhibition assay exhibited that 10d (FLT3, IC50: 5.3 nM) was a potent and selective FLT3 inhibitor. Furthermore, the pharmacokinetic experiments showed that 10d had good properties of oral bioavailability, Cmax, Tmax, T1/2 and AUC in mice, respectively. The in vivo study indicated that 10d could significantly suppress tumor growth in MV4-11 xenografts nude mice model and occupied with a commendable therapeutic window compared to sunitinib.
|
Displacement of [3H]-GR113808 from 5-HT4R in Dunkin-Hartley guinea pig straitum nuclear membranes after 2 hrs by filter binding method
|
Cavia porcellus
|
20.0
nM
|
|
Journal : MedChemComm
Title : Development of subnanomolar-affinity serotonin 5-HT<sub>4</sub> receptor ligands based on quinoline structures.
Year : 2018
Volume : 9
Issue : 9
First Page : 1466
Last Page : 1471
Authors : Castriconi F, Paolino M, Grisci G, Francini CM, Reale A, Giuliani G, Anzini M, Giorgi G, Mennuni L, Sabatini C, Lanza M, Caselli G, Cappelli A.
Abstract : Two small series of quinoline derivatives were designed starting from previously published quinoline derivatives <b>7a</b> and <b>b</b> in order to obtain information about their interaction with the 5-HT<sub>4</sub>R binding site. Initially, the structure of <b>7a</b> and <b>b</b> was modified by replacing their basic moiety with that of partial agonist <b>4</b> (ML10302) or with that of reference ligand <b>6</b> (RS-67-333). Then, the aromatic moieties of 4-quinolinecarboxylates <b>7a</b>, <b>d-f</b>, and <b>h-k</b> or 4-quinolinecarboxamides <b>7b</b>, <b>c</b>, and <b>g</b> were modified into those of 2-quinolinecarboxamides <b>9a-e</b>. Very interestingly, this structure-affinity relationship study led to the discovery of <b>7h-j</b> as novel 5-HT<sub>4</sub>R ligands showing <i>K</i> <sub>i</sub> values in the subnanomolar range. The structures of all these compounds contain the <i>N</i>-butyl-4-piperidinylmethyl substituent, which appear to behave as an optimized basic moiety in the interaction of these 4-quinolinecarboxylates with the 5-HT<sub>4</sub>R binding site. However, this basic moiety was ineffective in providing 5-HT<sub>4</sub>R affinity in the corresponding 4-quinolinecarboxamide <b>7g</b>, but it did in 2-quinolinecarboxamide ligands <b>9c-e</b>. Thus, a subtle interrelationship of several structural parameters appeared to play a major role in the interaction of the ligands with the 5-HT<sub>4</sub>R binding site. They include the kind of basic moiety, the position of the carbonyl linking group with respect to the aromatic moiety and its orientation, which could be affected by the presence of the intramolecular H-bond as in compounds <b>9c-e</b>.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
16.02
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-6.32
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
2.428
%
|
|
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
|
-0.13
%
|
|
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
|
-0.04
%
|
|
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
|
-0.13
%
|
|
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
|
-0.04
%
|
|
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.
