|
In vitro inhibition of alpha-1G T-type [Ca2+] channels expressed in HEK293 cells at 10 uM
|
Homo sapiens
|
95.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Dihydroquinazoline derivatives as novel selective T-type Ca2+ channel blockers.
Year : 2004
Volume : 14
Issue : 13
First Page : 3379
Last Page : 3384
Authors : Lee YS, Lee BH, Park SJ, Kang SB, Rhim H, Park JY, Lee JH, Jeong SW, Lee JY.
Abstract : For LVA T-type Ca2+ channel blockers, 3,4-dihydroquinazoline derivatives as new scaffolds were prepared and evaluated for the inhibitory activity against two members of the recombinant T-type Ca2+ channel family. Among them, 8a (KYS05001, IC50=0.9 microM) was nearly equipotent with mibefradil (IC50=0.84 microM) and inhibited LVA T-type Ca2+ channel with greater efficacy than HVA Ca2+ channel.
|
In vitro inhibitory effect on alpha-1H T-type [Ca2+] channels expressed in Xenopus oocytes at 100 uM
|
Homo sapiens
|
86.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Dihydroquinazoline derivatives as novel selective T-type Ca2+ channel blockers.
Year : 2004
Volume : 14
Issue : 13
First Page : 3379
Last Page : 3384
Authors : Lee YS, Lee BH, Park SJ, Kang SB, Rhim H, Park JY, Lee JH, Jeong SW, Lee JY.
Abstract : For LVA T-type Ca2+ channel blockers, 3,4-dihydroquinazoline derivatives as new scaffolds were prepared and evaluated for the inhibitory activity against two members of the recombinant T-type Ca2+ channel family. Among them, 8a (KYS05001, IC50=0.9 microM) was nearly equipotent with mibefradil (IC50=0.84 microM) and inhibited LVA T-type Ca2+ channel with greater efficacy than HVA Ca2+ channel.
|
Inhibition of human cytochrome P450 3A4
|
None
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Concentration of the compounds required for inhibition of HEK293 cells (alpha1G T-type)
|
Homo sapiens
|
840.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Dihydroquinazoline derivatives as novel selective T-type Ca2+ channel blockers.
Year : 2004
Volume : 14
Issue : 13
First Page : 3379
Last Page : 3384
Authors : Lee YS, Lee BH, Park SJ, Kang SB, Rhim H, Park JY, Lee JH, Jeong SW, Lee JY.
Abstract : For LVA T-type Ca2+ channel blockers, 3,4-dihydroquinazoline derivatives as new scaffolds were prepared and evaluated for the inhibitory activity against two members of the recombinant T-type Ca2+ channel family. Among them, 8a (KYS05001, IC50=0.9 microM) was nearly equipotent with mibefradil (IC50=0.84 microM) and inhibited LVA T-type Ca2+ channel with greater efficacy than HVA Ca2+ channel.
|
Inhibition of P-gp was determined using rhodamine-assay in human CaCo-2 cells
|
None
|
60.0
%
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Percent inhibition of N-type [Ca2+] channel (Alpha-1B) expressed in HEK293 cells at 10 uM
|
Homo sapiens
|
67.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of 3,4-dihydroquinazolines for selective T-type Ca2+ channel blockers.
Year : 2005
Volume : 15
Issue : 2
First Page : 283
Last Page : 286
Authors : Rhim H, Lee YS, Park SJ, Chung BY, Lee JY.
Abstract : We have synthesized 3,4-dihydroquinazoline derivatives for the potent and selective T-type Ca(2+) channel blockers and evaluated for their inhibitory activities against two subtypes T-type Ca(2+) channels and N-type Ca(2+) channels. Among them, 5b (KYS05044, IC(50)=0.56+/-0.10 microM) was identified as potent T-type Ca(2+) channel blocker with in vitro selectivity profile at meaningful level (T/N-type, SI=>100).
|
Percent inhibition of T-type [Ca2+] channel (alpha1G) expressed in HEK293 cells at 10 uM
|
Homo sapiens
|
95.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of 3,4-dihydroquinazolines for selective T-type Ca2+ channel blockers.
Year : 2005
Volume : 15
Issue : 2
First Page : 283
Last Page : 286
Authors : Rhim H, Lee YS, Park SJ, Chung BY, Lee JY.
Abstract : We have synthesized 3,4-dihydroquinazoline derivatives for the potent and selective T-type Ca(2+) channel blockers and evaluated for their inhibitory activities against two subtypes T-type Ca(2+) channels and N-type Ca(2+) channels. Among them, 5b (KYS05044, IC(50)=0.56+/-0.10 microM) was identified as potent T-type Ca(2+) channel blocker with in vitro selectivity profile at meaningful level (T/N-type, SI=>100).
|
Percent inhibition of T-type [Ca2+] channel (alpha1H) stably expressed in Xenopus oocytes at 100 uM
|
Homo sapiens
|
86.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of 3,4-dihydroquinazolines for selective T-type Ca2+ channel blockers.
Year : 2005
Volume : 15
Issue : 2
First Page : 283
Last Page : 286
Authors : Rhim H, Lee YS, Park SJ, Chung BY, Lee JY.
Abstract : We have synthesized 3,4-dihydroquinazoline derivatives for the potent and selective T-type Ca(2+) channel blockers and evaluated for their inhibitory activities against two subtypes T-type Ca(2+) channels and N-type Ca(2+) channels. Among them, 5b (KYS05044, IC(50)=0.56+/-0.10 microM) was identified as potent T-type Ca(2+) channel blocker with in vitro selectivity profile at meaningful level (T/N-type, SI=>100).
|
Ability to block calcium channel T type 3.2v expressed in Xenopus oocytes at 100 uM by two-microelectrode voltage-clamp method
|
Homo sapiens
|
86.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers.
Year : 2006
Volume : 16
Issue : 19
First Page : 5244
Last Page : 5248
Authors : Ku IW, Cho S, Doddareddy MR, Jang MS, Keum G, Lee JH, Chung BY, Kim Y, Rhim H, Kang SB.
Abstract : Morpholin-2-one-5-carboxamide derivatives were prepared by using the one-pot Ugi multicomponent reaction and evaluated for blocking effects on T- and N-type Ca(2+) channels. Among them, compound 5i produced the highest potency (IC(50)=0.45+/-0.02 microM), while compounds 5d, 5f, 5k, 5n, 5o, and 6m produced relatively high potency as well as selectivity on T-type Ca(2+) channels. These novel scaffolds showed potent and selective T-type Ca(2+) channel blocking activities.
|
Ability to block calcium channel T type 3.1v expressed in HEK293 cells at 10 uM by whole cell patch clamp method
|
Homo sapiens
|
89.8
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers.
Year : 2006
Volume : 16
Issue : 19
First Page : 5244
Last Page : 5248
Authors : Ku IW, Cho S, Doddareddy MR, Jang MS, Keum G, Lee JH, Chung BY, Kim Y, Rhim H, Kang SB.
Abstract : Morpholin-2-one-5-carboxamide derivatives were prepared by using the one-pot Ugi multicomponent reaction and evaluated for blocking effects on T- and N-type Ca(2+) channels. Among them, compound 5i produced the highest potency (IC(50)=0.45+/-0.02 microM), while compounds 5d, 5f, 5k, 5n, 5o, and 6m produced relatively high potency as well as selectivity on T-type Ca(2+) channels. These novel scaffolds showed potent and selective T-type Ca(2+) channel blocking activities.
|
Ability to block calcium channel N type 2.2v expressed in HEK293 cells at 10 uM by whole cell patch clamp method
|
Homo sapiens
|
57.4
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers.
Year : 2006
Volume : 16
Issue : 19
First Page : 5244
Last Page : 5248
Authors : Ku IW, Cho S, Doddareddy MR, Jang MS, Keum G, Lee JH, Chung BY, Kim Y, Rhim H, Kang SB.
Abstract : Morpholin-2-one-5-carboxamide derivatives were prepared by using the one-pot Ugi multicomponent reaction and evaluated for blocking effects on T- and N-type Ca(2+) channels. Among them, compound 5i produced the highest potency (IC(50)=0.45+/-0.02 microM), while compounds 5d, 5f, 5k, 5n, 5o, and 6m produced relatively high potency as well as selectivity on T-type Ca(2+) channels. These novel scaffolds showed potent and selective T-type Ca(2+) channel blocking activities.
|
Inhibition of alpha-1G T-type calcium channel expressed in HEK293 cells by electrophysiological method
|
Homo sapiens
|
840.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 3D pharmacophore based virtual screening of T-type calcium channel blockers.
Year : 2007
Volume : 15
Issue : 2
First Page : 1091
Last Page : 1105
Authors : Doddareddy MR, Choo H, Cho YS, Rhim H, Koh HY, Lee JH, Jeong SW, Pae AN.
Abstract : Virtual screening of the commercial databases was done by using a three dimensional pharmacophore previously developed for T-type calcium channel blockers using CATALYSTtrade mark program. Biological evaluation of 25 selected virtual hits resulted in the discovery of a highly potent compound VH04 with IC(50) value of 0.10 microM, eight times as potent as the known selective T-type calcium channel blocker, mibefradil. Search for similar compounds yielded several hits with micro-molar IC(50) values and high T-type calcium channel selectivity. Based on the structure of the virtual hits, small molecule libraries with novel scaffolds were designed, synthesis and biological evaluation of which are currently in progress. This result shows a successful example of ligand based drug discovery of potent T-type calcium channel blockers.
|
Inhibition of T type calcium channel subunit alpha-1H expressed in Xenopus oocytes at 100 uM by FDSS assay
|
Homo sapiens
|
86.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Lead discovery and optimization of T-type calcium channel blockers.
Year : 2007
Volume : 15
Issue : 3
First Page : 1409
Last Page : 1419
Authors : Park JH, Choi JK, Lee E, Lee JK, Rhim H, Seo SH, Kim Y, Doddareddy MR, Pae AN, Kang J, Roh EJ.
Abstract : A series of compounds were designed as T-type calcium channel blocker containing 6 or 5 pharmacophore features from structure-based virtual screening. To optimize the suggested structure, over 130 derivatives were synthesized and their inhibitory activities on T-type calcium channel were assayed using in vitro screening system with alpha1(G) and alpha1(H) clones. For the compounds with higher activities in FDSS assay system, the efficacy was measured by patch-clamp method. Among the library with 5 features, alkaneamide derivatives (7b, 9j, 11b, 11g, 11h) with 4-arylsubstituted piperazine showed better IC(50) values than Mibefradil.
|
Inhibition of T type calcium channel subunit alpha1G expressed in HEK293 cells assessed as effect on KCl-induced increase in intracellular calcium level at 10 uM by FDSS assay
|
Homo sapiens
|
78.17
%
|
|
Journal : Bioorg. Med. Chem.
Title : Lead discovery and optimization of T-type calcium channel blockers.
Year : 2007
Volume : 15
Issue : 3
First Page : 1409
Last Page : 1419
Authors : Park JH, Choi JK, Lee E, Lee JK, Rhim H, Seo SH, Kim Y, Doddareddy MR, Pae AN, Kang J, Roh EJ.
Abstract : A series of compounds were designed as T-type calcium channel blocker containing 6 or 5 pharmacophore features from structure-based virtual screening. To optimize the suggested structure, over 130 derivatives were synthesized and their inhibitory activities on T-type calcium channel were assayed using in vitro screening system with alpha1(G) and alpha1(H) clones. For the compounds with higher activities in FDSS assay system, the efficacy was measured by patch-clamp method. Among the library with 5 features, alkaneamide derivatives (7b, 9j, 11b, 11g, 11h) with 4-arylsubstituted piperazine showed better IC(50) values than Mibefradil.
|
Inhibition of T type calcium channel subunit alpha-1G expressed in HEK293 cells assessed as effect on T-type calcium currents at 10 uM by patch clamp method
|
Homo sapiens
|
95.9
%
|
|
Journal : Bioorg. Med. Chem.
Title : Lead discovery and optimization of T-type calcium channel blockers.
Year : 2007
Volume : 15
Issue : 3
First Page : 1409
Last Page : 1419
Authors : Park JH, Choi JK, Lee E, Lee JK, Rhim H, Seo SH, Kim Y, Doddareddy MR, Pae AN, Kang J, Roh EJ.
Abstract : A series of compounds were designed as T-type calcium channel blocker containing 6 or 5 pharmacophore features from structure-based virtual screening. To optimize the suggested structure, over 130 derivatives were synthesized and their inhibitory activities on T-type calcium channel were assayed using in vitro screening system with alpha1(G) and alpha1(H) clones. For the compounds with higher activities in FDSS assay system, the efficacy was measured by patch-clamp method. Among the library with 5 features, alkaneamide derivatives (7b, 9j, 11b, 11g, 11h) with 4-arylsubstituted piperazine showed better IC(50) values than Mibefradil.
|
Displacement of [3H]dofetilide from hERG expressed in HEK293 cells by SPA
|
Homo sapiens
|
353.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorescently labeled analogues of dofetilide as high-affinity fluorescence polarization ligands for the human ether-a-go-go-related gene (hERG) channel.
Year : 2007
Volume : 50
Issue : 13
First Page : 2931
Last Page : 2941
Authors : Singleton DH, Boyd H, Steidl-Nichols JV, Deacon M, Groot MJ, Price D, Nettleton DO, Wallace NK, Troutman MD, Williams C, Boyd JG.
Abstract : Novel fluorescent derivatives of dofetilide (1) have been synthesized. Analogues that feature a fluorescent probe attached through an aliphatic spacer to the central tertiary nitrogen of 1 have high affinity for the hERG channel, and affinity is dependent on both linker length and pendent dye. These variables have been optimized to generate Cy3B derivative 10e, which has hERG channel affinity equivalent to that of dofetilide. When bound to cell membranes expressing the hERG channel, 10e shows a robust increase in fluorescence polarization (FP) signal. In a FP binding assay using 10e as tracer ligand, Ki values for several known hERG channel blockers were measured and excellent agreement with the literature Ki values was observed over an affinity range of 2 nM to 3 muM. 10e blocks hERG channel current in electrophysiological patch clamp experiments, and computational docking experiments predict that the dofetilide core of 10e binds hERG channel in a conformation similar to that previously predicted for 1. These analogues enable high-throughput hERG channel binding assays that are rapid, economical, and predictive of test compounds' potential for prolonged QT liabilities.
|
Binding affinity at hERG expressed in HEK293 cells by fluorescence polarization assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Fluorescently labeled analogues of dofetilide as high-affinity fluorescence polarization ligands for the human ether-a-go-go-related gene (hERG) channel.
Year : 2007
Volume : 50
Issue : 13
First Page : 2931
Last Page : 2941
Authors : Singleton DH, Boyd H, Steidl-Nichols JV, Deacon M, Groot MJ, Price D, Nettleton DO, Wallace NK, Troutman MD, Williams C, Boyd JG.
Abstract : Novel fluorescent derivatives of dofetilide (1) have been synthesized. Analogues that feature a fluorescent probe attached through an aliphatic spacer to the central tertiary nitrogen of 1 have high affinity for the hERG channel, and affinity is dependent on both linker length and pendent dye. These variables have been optimized to generate Cy3B derivative 10e, which has hERG channel affinity equivalent to that of dofetilide. When bound to cell membranes expressing the hERG channel, 10e shows a robust increase in fluorescence polarization (FP) signal. In a FP binding assay using 10e as tracer ligand, Ki values for several known hERG channel blockers were measured and excellent agreement with the literature Ki values was observed over an affinity range of 2 nM to 3 muM. 10e blocks hERG channel current in electrophysiological patch clamp experiments, and computational docking experiments predict that the dofetilide core of 10e binds hERG channel in a conformation similar to that previously predicted for 1. These analogues enable high-throughput hERG channel binding assays that are rapid, economical, and predictive of test compounds' potential for prolonged QT liabilities.
|
Inhibition of T-type calcium channel Cav3.1 alpha-1G subunit expressed in HEK293 cells assessed as calcium current at 10 uM by patch-clamp assay
|
Homo sapiens
|
95.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent T-type calcium channel blocker.
Year : 2007
Volume : 17
Issue : 21
First Page : 5740
Last Page : 5743
Authors : Seo HN, Choi JY, Choe YJ, Kim Y, Rhim H, Lee SH, Kim J, Joo DJ, Lee JY.
Abstract : The intensive SAR study of 3,4-dihydroquinazoline series led to the most potent compound 10 (KYS05090: IC(50)=41+/-1 nM) against T-type calcium channel and its potency is nearly comparable to that of Kurtoxin. As a small organic molecule, this compound showed the highest blocking activity reported to date.
|
Inhibition of T-type calcium channel Cav3.1 alpha-1G subunit expressed in HEK293 cells assessed as calcium current at 10 uM by high throughput screening
|
Homo sapiens
|
77.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent T-type calcium channel blocker.
Year : 2007
Volume : 17
Issue : 21
First Page : 5740
Last Page : 5743
Authors : Seo HN, Choi JY, Choe YJ, Kim Y, Rhim H, Lee SH, Kim J, Joo DJ, Lee JY.
Abstract : The intensive SAR study of 3,4-dihydroquinazoline series led to the most potent compound 10 (KYS05090: IC(50)=41+/-1 nM) against T-type calcium channel and its potency is nearly comparable to that of Kurtoxin. As a small organic molecule, this compound showed the highest blocking activity reported to date.
|
Inhibition of N-type calcium channel Cav3.1 alpha-1B subunit expressed in HEK293 cells assessed as calcium current at 10 uM by patch-clamp assay
|
Homo sapiens
|
67.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent T-type calcium channel blocker.
Year : 2007
Volume : 17
Issue : 21
First Page : 5740
Last Page : 5743
Authors : Seo HN, Choi JY, Choe YJ, Kim Y, Rhim H, Lee SH, Kim J, Joo DJ, Lee JY.
Abstract : The intensive SAR study of 3,4-dihydroquinazoline series led to the most potent compound 10 (KYS05090: IC(50)=41+/-1 nM) against T-type calcium channel and its potency is nearly comparable to that of Kurtoxin. As a small organic molecule, this compound showed the highest blocking activity reported to date.
|
Inhibition of T-type calcium channel Cav3.2 expressed in HEK293 cells coexpressing alpha-1H subunit at 100 uM by two-electrode voltage clamp method
|
Homo sapiens
|
86.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel T-type calcium channel blockers.
Year : 2007
Volume : 17
Issue : 2
First Page : 471
Last Page : 475
Authors : Choi JY, Seo HN, Lee MJ, Park SJ, Park SJ, Jeon JY, Kang JH, Pae AN, Rhim H, Lee JY.
Abstract : 3,4-Dihydroquinazoline analogues substituted by N-methyl-N-(5-pyrrolidinopentyl)amine at the 2-position were synthesized and their blocking effects were evaluated for T- and N-type calcium channels. Compound 11b (KYS05080), compared to mibefradil (IC50=1.34+/-0.49 microM), was about 5-fold potent (IC50=0.26+/-0.01 microM) for T-type calcium channel (alpha1G) blocking and its selectivity of T/N-type was also improved (7.5 versus 1.4 of mibefradil).
|
Inhibition of T-type calcium channel Cav3.1 expressed in HEK293 cells co-expressing alpha1G subunit at 10 uM by whole-cell patch clamp method
|
Homo sapiens
|
95.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel T-type calcium channel blockers.
Year : 2007
Volume : 17
Issue : 2
First Page : 471
Last Page : 475
Authors : Choi JY, Seo HN, Lee MJ, Park SJ, Park SJ, Jeon JY, Kang JH, Pae AN, Rhim H, Lee JY.
Abstract : 3,4-Dihydroquinazoline analogues substituted by N-methyl-N-(5-pyrrolidinopentyl)amine at the 2-position were synthesized and their blocking effects were evaluated for T- and N-type calcium channels. Compound 11b (KYS05080), compared to mibefradil (IC50=1.34+/-0.49 microM), was about 5-fold potent (IC50=0.26+/-0.01 microM) for T-type calcium channel (alpha1G) blocking and its selectivity of T/N-type was also improved (7.5 versus 1.4 of mibefradil).
|
Inhibition of N-type calcium channel expressed in HEK293 cells co-expressing Alpha-1B subunit at 10 uM
|
Homo sapiens
|
67.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel T-type calcium channel blockers.
Year : 2007
Volume : 17
Issue : 2
First Page : 471
Last Page : 475
Authors : Choi JY, Seo HN, Lee MJ, Park SJ, Park SJ, Jeon JY, Kang JH, Pae AN, Rhim H, Lee JY.
Abstract : 3,4-Dihydroquinazoline analogues substituted by N-methyl-N-(5-pyrrolidinopentyl)amine at the 2-position were synthesized and their blocking effects were evaluated for T- and N-type calcium channels. Compound 11b (KYS05080), compared to mibefradil (IC50=1.34+/-0.49 microM), was about 5-fold potent (IC50=0.26+/-0.01 microM) for T-type calcium channel (alpha1G) blocking and its selectivity of T/N-type was also improved (7.5 versus 1.4 of mibefradil).
|
Antagonist activity at human alpha1H T-type calcium channel expressed in HEK293 cells by patch clamp technique
|
Homo sapiens
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and SAR of selective T-type calcium channel antagonists containing a biaryl sulfonamide core.
Year : 2008
Volume : 18
Issue : 2
First Page : 474
Last Page : 478
Authors : Hangeland JJ, Cheney DL, Friends TJ, Swartz S, Levesque PC, Rich AJ, Sun L, Bridal TR, Adam LP, Normandin DE, Murugesan N, Ewing WR.
Abstract : T-type calcium channel antagonists were designed using a protocol involving the program SPROUT and constrained by a ComFA-based pharmacophore model. Scaffolds generated by SPROUT were evaluated based on their ability to be translated into structures that were synthetically tractable. From this exercise, a novel series of potent and selective T-type channel antagonists containing a biaryl sulfonamide core were discovered.
|
Antagonist activity at T type calcium channel alpha1G expressed in HEK293 cells assessed as inhibition of peak currents at 10 uM by whole-cell patch-clamp method
|
None
|
95.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of alpha,alpha'-disubstituted phenylacetate derivatives for T-type calcium channel blockers.
Year : 2008
Volume : 18
Issue : 15
First Page : 4424
Last Page : 4427
Authors : Lee HK, Lee YS, Roh EJ, Rhim H, Lee JY, Shin KJ.
Abstract : We have synthesized and evaluated alpha,alpha'-disubstituted phenylacetate derivatives that were designed as T-type calcium channel blockers. Among them, compound 10e (IC(50)=8.17+/-0.48nM) showed the most potent T-type calcium current blocking activity and higher potency than Mibefradil (IC(50)=1.34+/-0.49microM). The PK profile and subtype selectivity over L-type calcium channel were satisfied for further animal assay using disease model.
|
Inhibition of T-type calcium channel alpha1I by FLIPR
|
None
|
126.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels.
Year : 2008
Volume : 51
Issue : 20
First Page : 6471
Last Page : 6477
Authors : Yang ZQ, Barrow JC, Shipe WD, Schlegel KA, Shu Y, Yang FV, Lindsley CW, Rittle KE, Bock MG, Hartman GD, Uebele VN, Nuss CE, Fox SV, Kraus RL, Doran SM, Connolly TM, Tang C, Ballard JE, Kuo Y, Adarayan ED, Prueksaritanont T, Zrada MM, Marino MJ, Graufelds VK, DiLella AG, Reynolds IJ, Vargas HM, Bunting PB, Woltmann RF, Magee MM, Koblan KS, Renger JJ.
Abstract : The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 microM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.
|
Inhibition of human ERG
|
Homo sapiens
|
806.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels.
Year : 2008
Volume : 51
Issue : 20
First Page : 6471
Last Page : 6477
Authors : Yang ZQ, Barrow JC, Shipe WD, Schlegel KA, Shu Y, Yang FV, Lindsley CW, Rittle KE, Bock MG, Hartman GD, Uebele VN, Nuss CE, Fox SV, Kraus RL, Doran SM, Connolly TM, Tang C, Ballard JE, Kuo Y, Adarayan ED, Prueksaritanont T, Zrada MM, Marino MJ, Graufelds VK, DiLella AG, Reynolds IJ, Vargas HM, Bunting PB, Woltmann RF, Magee MM, Koblan KS, Renger JJ.
Abstract : The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 microM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.
|
Displacement of [3H]diltiazem from L-type calcium channel in rabbit muscle cells
|
Oryctolagus cuniculus
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels.
Year : 2008
Volume : 51
Issue : 20
First Page : 6471
Last Page : 6477
Authors : Yang ZQ, Barrow JC, Shipe WD, Schlegel KA, Shu Y, Yang FV, Lindsley CW, Rittle KE, Bock MG, Hartman GD, Uebele VN, Nuss CE, Fox SV, Kraus RL, Doran SM, Connolly TM, Tang C, Ballard JE, Kuo Y, Adarayan ED, Prueksaritanont T, Zrada MM, Marino MJ, Graufelds VK, DiLella AG, Reynolds IJ, Vargas HM, Bunting PB, Woltmann RF, Magee MM, Koblan KS, Renger JJ.
Abstract : The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 microM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.
|
Inhibition of T-type calcium channel alpha1G expressed in human HEK293 cells assessed as inhibition of KCl-induced decrease in calcium level at 10 uM after 60 mins by FDSS6000 assay
|
None
|
78.92
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 1,4-diazepane derivatives as T-type calcium channel blockers.
Year : 2010
Volume : 20
Issue : 9
First Page : 2705
Last Page : 2708
Authors : Gu SJ, Lee JK, Pae AN, Chung HJ, Rhim H, Han SY, Min SJ, Cho YS.
Abstract : We have synthesized and biologically evaluated 1,4-diazepane derivatives as T-type calcium channel blockers. In this study, we discovered compound 4s, a potential T-type calcium channel blocker with good selectivity over hERG and N-type calcium channels. In addition, it exhibited favorable pharmacokinetic characteristics for further investigation of T-type calcium channel related diseases.
|
Inhibition of T-type CaV3.1 channel expressed in HEK293 cells assessed as inhibition of calcium current at 10 uM by fluorescence based HTS FDSS6000 assay
|
None
|
80.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of oxazole derivatives as T-type calcium channel blockers.
Year : 2010
Volume : 20
Issue : 14
First Page : 4219
Last Page : 4222
Authors : Lee JE, Koh HY, Seo SH, Baek YY, Rhim H, Cho YS, Choo H, Pae AN.
Abstract : T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pain. In this study, as a part of our ongoing efforts to develop potent T-type calcium channel blockers, we designed oxazole derivatives substituted with arylpiperazinylalkylamines. The oxazoles were synthesized in a convenient convergent synthetic method, and biologically evaluated against alpha(1G) (Ca(V)3.1) T-type calcium channel. Among total 41 oxazole compounds synthesized, the most active one was the compound 10-35 with an IC(50) value of 0.65 microM, which is comparable with that of mibefradil.
|
Inhibition of T-type CaV3.1 channel expressed in HEK293 cells assessed as inhibition of calcium current by manual patch-clamp assay
|
None
|
860.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of oxazole derivatives as T-type calcium channel blockers.
Year : 2010
Volume : 20
Issue : 14
First Page : 4219
Last Page : 4222
Authors : Lee JE, Koh HY, Seo SH, Baek YY, Rhim H, Cho YS, Choo H, Pae AN.
Abstract : T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pain. In this study, as a part of our ongoing efforts to develop potent T-type calcium channel blockers, we designed oxazole derivatives substituted with arylpiperazinylalkylamines. The oxazoles were synthesized in a convenient convergent synthetic method, and biologically evaluated against alpha(1G) (Ca(V)3.1) T-type calcium channel. Among total 41 oxazole compounds synthesized, the most active one was the compound 10-35 with an IC(50) value of 0.65 microM, which is comparable with that of mibefradil.
|
Inhibition of T-type CaV3.1 channel expressed in HEK293 cells assessed as inhibition of calcium current by automated patch-clamp assay
|
None
|
830.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of oxazole derivatives as T-type calcium channel blockers.
Year : 2010
Volume : 20
Issue : 14
First Page : 4219
Last Page : 4222
Authors : Lee JE, Koh HY, Seo SH, Baek YY, Rhim H, Cho YS, Choo H, Pae AN.
Abstract : T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pain. In this study, as a part of our ongoing efforts to develop potent T-type calcium channel blockers, we designed oxazole derivatives substituted with arylpiperazinylalkylamines. The oxazoles were synthesized in a convenient convergent synthetic method, and biologically evaluated against alpha(1G) (Ca(V)3.1) T-type calcium channel. Among total 41 oxazole compounds synthesized, the most active one was the compound 10-35 with an IC(50) value of 0.65 microM, which is comparable with that of mibefradil.
|
Inhibition of N-type Alpha-1B channel expressed in HEK293 cells by whole-cell patch-clamp method
|
None
|
67.63
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and T-type calcium channel blocking activity of novel diphenylpiperazine compounds, and evaluation of in vivo analgesic activity.
Year : 2010
Volume : 18
Issue : 16
First Page : 5938
Last Page : 5944
Authors : Kam YL, Rhee HK, Rhim H, Back SK, Na HS, Choo HY.
Abstract : Novel diphenylpiperazine derivatives were synthesized and evaluated for their inhibitory activity against T-type calcium channel by whole-cell patch clamp recordings on HEK293 cells. Among the test compounds, 2 and 3d were effective in decreasing the response to formalin in both the first and second phases and demonstrated antiallodynic effects in a rat model of neuropathic pain.
|
Antimicrobial activity against Plasmodium yoelii 265 liver infected in mammalian hepatocytes after 48 hrs
|
Plasmodium yoelii yoelii
|
0.873
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : New active drugs against liver stages of Plasmodium predicted by molecular topology.
Year : 2008
Volume : 52
Issue : 4
First Page : 1215
Last Page : 1220
Authors : Mahmoudi N, Garcia-Domenech R, Galvez J, Farhati K, Franetich JF, Sauerwein R, Hannoun L, Derouin F, Danis M, Mazier D.
Abstract : We conducted a quantitative structure-activity relationship (QSAR) study based on a database of 127 compounds previously tested against the liver stage of Plasmodium yoelii in order to develop a model capable of predicting the in vitro antimalarial activities of new compounds. Topological indices were used as structural descriptors, and their relation to antimalarial activity was determined by using linear discriminant analysis. A topological model consisting of two discriminant functions was created. The first function discriminated between active and inactive compounds, and the second identified the most active among the active compounds. The model was then applied sequentially to a large database of compounds with unknown activity against liver stages of Plasmodium. Seventeen drugs that were predicted to be active or inactive were selected for testing against the hepatic stage of P. yoelii in vitro. Antiretroviral, antifungal, and cardiotonic drugs were found to be highly active (nanomolar 50% inhibitory concentration values), and two ionophores completely inhibited parasite development. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed on hepatocyte cultures for all compounds, and none of these compounds were toxic in vitro. For both ionophores, the same in vitro assay as those for P. yoelii has confirmed their in vitro activities on Plasmodium falciparum. A similar topological model was used to estimate the octanol/water partition of each compound. These results demonstrate the utility of the QSAR and molecular topology approaches for identifying new drugs that are active against the hepatic stage of malaria parasites. We also show the remarkable efficacy of some drugs that were not previously reported to have antiparasitic activity.
|
Antagonist activity against T-type calcium channel subunit alpha-1H assessed as inactivation of channel current by cell based patch clamp assay
|
None
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, syntheses, and SAR of 2,8-diazaspiro[4.5]decanones as T-type calcium channel antagonists.
Year : 2010
Volume : 20
Issue : 22
First Page : 6375
Last Page : 6378
Authors : Fritch PC, Krajewski J.
Abstract : It was hypothesized that an appropriately substituted 2,8-diazaspiro[4.5]decan-1-one could effectively approximate a 5-feature T-type pharmacophore model published in the literature. Compounds were designed and synthesized to test our hypothesis and were found to be potent T-type calcium channel inhibitors with modest selectivity over L-type calcium channels. The synthesis and SAR of the series is described.
|
Antagonist activity against L-type calcium channel subunit alpha-1C assessed as inactivation of channel current by cell based patch clamp assay
|
None
|
416.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, syntheses, and SAR of 2,8-diazaspiro[4.5]decanones as T-type calcium channel antagonists.
Year : 2010
Volume : 20
Issue : 22
First Page : 6375
Last Page : 6378
Authors : Fritch PC, Krajewski J.
Abstract : It was hypothesized that an appropriately substituted 2,8-diazaspiro[4.5]decan-1-one could effectively approximate a 5-feature T-type pharmacophore model published in the literature. Compounds were designed and synthesized to test our hypothesis and were found to be potent T-type calcium channel inhibitors with modest selectivity over L-type calcium channels. The synthesis and SAR of the series is described.
|
Inhibition of T-type alpha1G calcium channel expressed in HEK293 cells assessed as Kcl-induced depolarization at 10 uM
|
None
|
78.92
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Facile synthesis and biological evaluation of 3,3-diphenylpropanoyl piperazines as T-type calcium channel blockers.
Year : 2011
Volume : 21
Issue : 1
First Page : 215
Last Page : 219
Authors : Choi YH, Baek du J, Seo SH, Lee JK, Pae AN, Cho YS, Min SJ.
Abstract : We have developed a facile synthesis of 3,3-diphenylpropanamides using Meldrum's acid derivatives as amide coupling components. The in vitro biological evaluation of the title compounds led to the identification of compound 1h, which has good inhibitory activity against T-type calcium channel (IC(50) = 0.83 μM).
|
Inhibition of human Cav3.1 alpha1G expressed in HEK293 cells assessed as inhibition of calcium influx by FLIPR assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological evaluation of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives as novel antihypertensive agents.
Year : 2011
Volume : 19
Issue : 18
First Page : 5628
Last Page : 5638
Authors : Watanuki S, Matsuura K, Tomura Y, Okada M, Okazaki T, Ohta M, Tsukamoto S.
Abstract : We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that dialkyl substituents at the benzylic position play an important role in increasing inhibitory activity. Oral administration of N-[2-ethyl-2-(4-fluorophenyl)butyl]-1-(2-phenylethyl)piperidine-4-carboxamide (20d) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.
|
Inhibition of T-type calcium channel alpha1G expressed in human HEK293 cells assessed as KCl-induced depolarization at 10 uM after 60 mins by FDSS6000 assay
|
None
|
78.95
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 4-piperidinecarboxylate and 4-piperidinecyanide derivatives for T-type calcium channel blockers.
Year : 2011
Volume : 21
Issue : 19
First Page : 5910
Last Page : 5915
Authors : Woo HM, Lee YS, Roh EJ, Seo SH, Song CM, Chung HJ, Pae AN, Shin KJ.
Abstract : To obtain selective and potent inhibitor for T-type calcium channel by ligand based drug design, 4-piperidinecarboxylate and 4-piperidinecyanide derivatives were prepared and evaluated for in vitro and in vivo activity against α(1G) calcium channel. Among them, several compounds showed good T-type calcium channel inhibitory activity and minimal off-target activity over hERG channel (% inhibition at 10 μM=61.85-71.99, hERG channel IC(50)=1.57 ± 0.14-4.98 ± 0.36 μM). Selected compound 31a was evaluated on SNL model of neuropathic pain and showed inhibitory effect on mechanical allodynia.
|
Antimalarial activity against liver stages of Plasmodium yoelii yoelii
|
Plasmodium yoelii yoelii
|
0.873
nM
|
|
Journal : J. Med. Chem.
Title : Targeting the liver stage of malaria parasites: a yet unmet goal.
Year : 2012
Volume : 55
Issue : 3
First Page : 995
Last Page : 1012
Authors : Rodrigues T, Prudêncio M, Moreira R, Mota MM, Lopes F.
|
Reversible inhibition of CYP3A4
|
None
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks.
Year : 2012
Volume : 55
Issue : 11
First Page : 4896
Last Page : 4933
Authors : Orr ST, Ripp SL, Ballard TE, Henderson JL, Scott DO, Obach RS, Sun H, Kalgutkar AS.
|
Inhibition of human recombinant CYP2D6-mediated 7-methoxy-4(aminomethyl)-coumarine degradation
|
Homo sapiens
|
63.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of N-[[1-[2-(tert-butylcarbamoylamino)ethyl]-4-(hydroxymethyl)-4-piperidyl]methyl]-3,5-dichloro-benzamide as a selective T-type calcium channel (Cav3.2) inhibitor.
Year : 2013
Volume : 23
Issue : 1
First Page : 119
Last Page : 124
Authors : Giordanetto F, Wållberg A, Knerr L, Selmi N, Ullah V, Thorstensson F, Lindelöf Å, Karlsson S, Nikitidis G, Llinas A, Wang QD, Lindqvist A, Högberg G, Lindhardt E, Åstrand A, Duker G.
Abstract : The T-type calcium channel inhibitor Mibefradil was reported to protect the heart from atrial remodeling, a key process involved in the development of atrial fibrillation and arrhythmias. Mibefradil is not a selective T-type calcium channel inhibitor and also affects the function of different ion channels. Our aim was to develop a selective T-type calcium channel inhibitor to validate the importance of T-type-related pharmacology in atrial fibrillation. Structural optimisation of a previously disclosed hit series focussed on minimising exposure to the central nervous system and improving pharmacokinetic properties, while maintain adequate potency and selectivity. This resulted in the design of N-[[1-[2-(tert-butylcarbamoylamino)ethyl]-4-(hydroxymethyl)-4-piperidyl]methyl]-3,5-dichloro-benzamide, a novel, selective, peripherally restricted chemical probe to verify the role of T-type calcium channel inhibition on atrial fibrillation protection.
|
Inhibition of alpha-1G calcium channel in human HEK293 cells at 10 uM by whole-cell patch-clamp method
|
Homo sapiens
|
81.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 1-(2-hydroxy-3-phenyloxypropyl)piperazine derivatives as T-type calcium channel blockers.
Year : 2013
Volume : 23
Issue : 6
First Page : 1887
Last Page : 1890
Authors : Park JE, Ji WK, Jang JW, Pae AN, Choi K, Choi KH, Kang J, Roh EJ.
Abstract : To obtain selective and potent inhibitor for T-type calcium channel by ligand based drug design, 2-hydroxy-3-phenoxypropyl piperazine derivatives were synthesized and evaluated for in vitro activities. Compound 6m and 6q showed high selectivity over hERG channel (IC50 ratio of hERG/α1G6m=8.5, 6q=18.38) and they were subjected to measure pharmacokinetics profiles. Among them compound 6m showed an excellent pharmacokinetic profile in rats.
|
Inhibition of alpha-1G calcium channel in human HEK293 cells by whole-cell patch-clamp method
|
Homo sapiens
|
830.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 1-(2-hydroxy-3-phenyloxypropyl)piperazine derivatives as T-type calcium channel blockers.
Year : 2013
Volume : 23
Issue : 6
First Page : 1887
Last Page : 1890
Authors : Park JE, Ji WK, Jang JW, Pae AN, Choi K, Choi KH, Kang J, Roh EJ.
Abstract : To obtain selective and potent inhibitor for T-type calcium channel by ligand based drug design, 2-hydroxy-3-phenoxypropyl piperazine derivatives were synthesized and evaluated for in vitro activities. Compound 6m and 6q showed high selectivity over hERG channel (IC50 ratio of hERG/α1G6m=8.5, 6q=18.38) and they were subjected to measure pharmacokinetics profiles. Among them compound 6m showed an excellent pharmacokinetic profile in rats.
|
Inhibition of t-type Cav3.1 channel (unknown origin) expressed in HEK293 cells assessed as inhibition of 50 ms depolarizing voltage step-induced current by whole cell patch-clamp method
|
Homo sapiens
|
560.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro cytotoxicity on human ovarian cancer cells by T-type calcium channel blockers.
Year : 2013
Volume : 23
Issue : 24
First Page : 6656
Last Page : 6662
Authors : Jang SJ, Choi HW, Choi DL, Cho S, Rim HK, Choi HE, Kim KS, Huang M, Rhim H, Lee KT, Lee JY.
Abstract : The growth inhibition of human cancer cells via T-type Ca(2+) channel blockade has been well known. Herein, a series of new 3,4-dihydroquinazoline derivatives were synthesized via a brief SAR study on KYS05090 template and evaluated for both T-type Ca(2+) channel (Cav3.1) blockade and cytotoxicity on three human ovarian cancer cells (SK-OV-3, A2780 and A2780-T). Most of compounds except 6i generally exhibited more potent cytotoxicity on SK-OV-3 than mibefradil as a positive control regardless of the degree of T-type channel blockade. In particular, eight compounds (KYS05090, 6a and 6c-6h) showing strong channel blockade exhibited almost equal and more potent cytotoxicity on A2780 when compared to mibefradil. On A2780-T paclitaxel-resistant human ovarian carcinoma, two compounds (KYS05090 and 6d) were 20-fold more active than mibefradil. With respect to cell cycle arrest effect on A2780 and A2780-T cells, KYS05090 induced large proportion of sub-G1 phase in the cell cycle progression of A2780 and A2780-T, meaning the induction of cancer cell death instead of cell cycle arrest via blocking T-type Ca(2+) channel. Among new analogues, compounds 6g and 6h induced cell cycle arrest at G1 phase of A2780 and A2780-T cells in dose-dependent manner and exhibited strong anti-proliferation effects of ovarian cancer cells by blocking T-type Ca(2+) channel. Furthermore, 6g and 6h possessing strong cytotoxic effects could induce apoptosis of A2780 cells, which was detected by confocal micrographs using DAPI staining.
|
Inhibition of t-type Cav3.1 channel (unknown origin) expressed in HEK293 cells assessed as inhibition of 50 ms depolarizing voltage step-induced current at 1 uM by whole cell patch-clamp method relative to control
|
Homo sapiens
|
55.1
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro cytotoxicity on human ovarian cancer cells by T-type calcium channel blockers.
Year : 2013
Volume : 23
Issue : 24
First Page : 6656
Last Page : 6662
Authors : Jang SJ, Choi HW, Choi DL, Cho S, Rim HK, Choi HE, Kim KS, Huang M, Rhim H, Lee KT, Lee JY.
Abstract : The growth inhibition of human cancer cells via T-type Ca(2+) channel blockade has been well known. Herein, a series of new 3,4-dihydroquinazoline derivatives were synthesized via a brief SAR study on KYS05090 template and evaluated for both T-type Ca(2+) channel (Cav3.1) blockade and cytotoxicity on three human ovarian cancer cells (SK-OV-3, A2780 and A2780-T). Most of compounds except 6i generally exhibited more potent cytotoxicity on SK-OV-3 than mibefradil as a positive control regardless of the degree of T-type channel blockade. In particular, eight compounds (KYS05090, 6a and 6c-6h) showing strong channel blockade exhibited almost equal and more potent cytotoxicity on A2780 when compared to mibefradil. On A2780-T paclitaxel-resistant human ovarian carcinoma, two compounds (KYS05090 and 6d) were 20-fold more active than mibefradil. With respect to cell cycle arrest effect on A2780 and A2780-T cells, KYS05090 induced large proportion of sub-G1 phase in the cell cycle progression of A2780 and A2780-T, meaning the induction of cancer cell death instead of cell cycle arrest via blocking T-type Ca(2+) channel. Among new analogues, compounds 6g and 6h induced cell cycle arrest at G1 phase of A2780 and A2780-T cells in dose-dependent manner and exhibited strong anti-proliferation effects of ovarian cancer cells by blocking T-type Ca(2+) channel. Furthermore, 6g and 6h possessing strong cytotoxic effects could induce apoptosis of A2780 cells, which was detected by confocal micrographs using DAPI staining.
|
Inhibition of T-type CaV3.1 channel (unknown origin) expressed in HEK293 cells assessed as inhibition of calcium current at 1 uM by whole cell patch-clamp method
|
Homo sapiens
|
55.1
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of cellular proliferation and induction of apoptosis in human lung adenocarcinoma A549 cells by T-type calcium channel antagonist.
Year : 2014
Volume : 24
Issue : 6
First Page : 1565
Last Page : 1570
Authors : Choi DL, Jang SJ, Cho S, Choi HE, Rim HK, Lee KT, Lee JY.
Abstract : The anti-proliferative and apoptotic activities of new T-type calcium channel antagonist, 6e (BK10040) on human lung adenocarcinoma A549 cells were investigated. The MTT assay results indicated that BK10040 was cytotoxic against human lung adenocarcinoma (A549) and pancreatic cancer (MiaPaCa2) cells in a dose-dependent manner with IC50 of 2.25 and 0.93μM, respectively, which is ca. 2-fold more potent than lead compound KYS05090 despite of its decreased T-type calcium channel blockade. As a mode of action for cytotoxic effect of BK10040 on lung cancer (A549) cells, this cancer cell death was found to have the typical features of apoptosis, as evidenced by the accumulation of positive cells for annexin V. In addition, BK10040 triggered the activations of caspases 3 and 9, and the cleavages of poly (ADP-ribose) polymerase (PARP). Moreover, the treatment with z-VAD-fmk (a broad spectrum caspase inhibitor) significantly prevented BK10040-induced apoptosis. Based on these results, BK10040 may be used as a potential therapeutic agent for human lung cancer via the potent apoptotic activity.
|
Inhibition of T-type CaV3.1 channel (unknown origin) expressed in HEK293 cells assessed as inhibition of calcium current by whole cell patch-clamp method
|
Homo sapiens
|
560.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of cellular proliferation and induction of apoptosis in human lung adenocarcinoma A549 cells by T-type calcium channel antagonist.
Year : 2014
Volume : 24
Issue : 6
First Page : 1565
Last Page : 1570
Authors : Choi DL, Jang SJ, Cho S, Choi HE, Rim HK, Lee KT, Lee JY.
Abstract : The anti-proliferative and apoptotic activities of new T-type calcium channel antagonist, 6e (BK10040) on human lung adenocarcinoma A549 cells were investigated. The MTT assay results indicated that BK10040 was cytotoxic against human lung adenocarcinoma (A549) and pancreatic cancer (MiaPaCa2) cells in a dose-dependent manner with IC50 of 2.25 and 0.93μM, respectively, which is ca. 2-fold more potent than lead compound KYS05090 despite of its decreased T-type calcium channel blockade. As a mode of action for cytotoxic effect of BK10040 on lung cancer (A549) cells, this cancer cell death was found to have the typical features of apoptosis, as evidenced by the accumulation of positive cells for annexin V. In addition, BK10040 triggered the activations of caspases 3 and 9, and the cleavages of poly (ADP-ribose) polymerase (PARP). Moreover, the treatment with z-VAD-fmk (a broad spectrum caspase inhibitor) significantly prevented BK10040-induced apoptosis. Based on these results, BK10040 may be used as a potential therapeutic agent for human lung cancer via the potent apoptotic activity.
|
Inhibition of Na channel (species unknown)
|
None
|
980.0
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 voltage-gated L-type Ca channel (species unknown)
|
None
|
156.0
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 Cav1.2 current measured using QPatch automatic path clamp system in CHO cells expressing Cav1.2, beta-2 and alpha-2/delta-1 subunits
|
Cricetulus griseus
|
510.0
nM
|
|
Journal : Scientific Reports
Title : MICE models: superior to the HERG model in predicting Torsade de Pointes.
Year : 2013
Volume : 3
First Page : 1
Last Page : 7
Authors : Kramer J, Obejero-Paz CA, Myatt G, Kuryshev YA, Bruening-Wright A, Verducci JS, Brown AM.
Abstract : Drug-induced block of the cardiac hERG (human Ether-à-go-go-Related Gene) potassium channel delays cardiac repolarization and increases the risk of Torsade de Pointes (TdP), a potentially lethal arrhythmia. A positive hERG assay has been embraced by regulators as a non-clinical predictor of TdP despite a discordance of about 30%. To test whether assaying concomitant block of multiple ion channels (Multiple Ion Channel Effects or MICE) improves predictivity we measured the concentration-responses of hERG, Nav1.5 and Cav1.2 currents for 32 torsadogenic and 23 non-torsadogenic drugs from multiple classes. We used automated gigaseal patch clamp instruments to provide higher throughput along with accuracy and reproducibility. Logistic regression models using the MICE assay showed a significant reduction in false positives (Type 1 errors) and false negatives (Type 2 errors) when compared to the hERG assay. The best MICE model only required a comparison of the blocking potencies between hERG and Cav1.2.
|
Inhibition of recombinant CYP3A4 (unknown origin) expressed in baculosomes at 10 uM measured after 1.5 min in presence of 1 mM NADPH
|
Homo sapiens
|
20.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Mechanism-based inactivation of cytochrome P450 3A4 by mibefradil through heme destruction.
Year : 2011
Volume : 39
Issue : 7
First Page : 1188
Last Page : 1195
Authors : Foti RS, Rock DA, Pearson JT, Wahlstrom JL, Wienkers LC.
Abstract : Mibefradil (Posicor) was developed as a calcium channel blocker for the treatment of chronic hypertension. The compound was withdrawn from the market in 1998 because of the potential for rhabdomyolysis, renal failure, or bradycardia when it was coadministered with other drugs. Mibefradil has previously been shown to be a potent reversible (IC(50) = 0.3-2 μM) and mechanism-based (K(i) = 2.3 μM; k(inact) = 0.4 min(-1)) inhibitor of CYP3A4-catalyzed statin metabolism. At present, the mechanism of CYP3A4 inactivation by mibefradil is not known. Mechanism-based inactivation experiments and spectral studies were used to examine the mechanism of CYP3A4 inactivation by mibefradil and its major metabolite, des-methoxyacetyl mibefradil (Ro 40-5966), in vitro. Both mibefradil and Ro 40-5966 were shown to exhibit type I binding characteristics (K(s) = 0.69 ± 0.06 and 1.39 ± 0.04 μM, respectively) toward CYP3A4. Complete K(i)/k(inact) experiments were performed, revealing a rapid and irreversible decrease in CYP3A4-catalyzed 1'-hydroxymidazolam formation. Approximately 70% of CYP3A4 activity was lost in the first minute of incubation with mibefradil, and inactivation was nonlinear after 2 min. Ro 40-5966 also resulted in time-dependent inhibition of CYP3A4, albeit to a lesser extent than mibefradil. The decrease in CYP3A4 activity in the presence of mibefradil and NADPH was subsequently shown to have a good correlation with the time-dependent loss of CO binding, which, coupled with the lack of stable heme and/or apoprotein adducts, suggests heme destruction as the mechanism of inactivation of CYP3A4 by mibefradil.
|
Inhibition of recombinant CYP3A4 (unknown origin) expressed in baculosomes in presence of 1 mM NADPH
|
Homo sapiens
|
280.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Mechanism-based inactivation of cytochrome P450 3A4 by mibefradil through heme destruction.
Year : 2011
Volume : 39
Issue : 7
First Page : 1188
Last Page : 1195
Authors : Foti RS, Rock DA, Pearson JT, Wahlstrom JL, Wienkers LC.
Abstract : Mibefradil (Posicor) was developed as a calcium channel blocker for the treatment of chronic hypertension. The compound was withdrawn from the market in 1998 because of the potential for rhabdomyolysis, renal failure, or bradycardia when it was coadministered with other drugs. Mibefradil has previously been shown to be a potent reversible (IC(50) = 0.3-2 μM) and mechanism-based (K(i) = 2.3 μM; k(inact) = 0.4 min(-1)) inhibitor of CYP3A4-catalyzed statin metabolism. At present, the mechanism of CYP3A4 inactivation by mibefradil is not known. Mechanism-based inactivation experiments and spectral studies were used to examine the mechanism of CYP3A4 inactivation by mibefradil and its major metabolite, des-methoxyacetyl mibefradil (Ro 40-5966), in vitro. Both mibefradil and Ro 40-5966 were shown to exhibit type I binding characteristics (K(s) = 0.69 ± 0.06 and 1.39 ± 0.04 μM, respectively) toward CYP3A4. Complete K(i)/k(inact) experiments were performed, revealing a rapid and irreversible decrease in CYP3A4-catalyzed 1'-hydroxymidazolam formation. Approximately 70% of CYP3A4 activity was lost in the first minute of incubation with mibefradil, and inactivation was nonlinear after 2 min. Ro 40-5966 also resulted in time-dependent inhibition of CYP3A4, albeit to a lesser extent than mibefradil. The decrease in CYP3A4 activity in the presence of mibefradil and NADPH was subsequently shown to have a good correlation with the time-dependent loss of CO binding, which, coupled with the lack of stable heme and/or apoprotein adducts, suggests heme destruction as the mechanism of inactivation of CYP3A4 by mibefradil.
|
Inhibition of CYP2D6 in human liver microsomes using bufuralol substrate by LC-MS/MS method
|
Homo sapiens
|
840.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Discovery and characterization of novel, potent, and selective cytochrome P450 2J2 inhibitors.
Year : 2013
Volume : 41
Issue : 1
First Page : 60
Last Page : 71
Authors : Ren S, Zeng J, Mei Y, Zhang JZ, Yan SF, Fei J, Chen L.
Abstract : Cytochrome P450 (CYP) 2J2 is one of the human CYPs involved in phase I xenobiotics metabolism. It is mainly expressed in extrahepatic tissues, including intestine and cardiovascular systems. The general role of CYP2J2 in drug metabolism is not yet fully understood, and the recent discovery that CYP2J2 can metabolize a wide range of structurally diverse drugs and its primary distribution in the intestine suggest its potentially indispensable role in first-pass intestinal metabolism and involvement in drug-drug interaction. To fully characterize its role in drug metabolism, selective and potent inhibitors of CYP2J2 are necessary tools. In the current study, 69 known drugs were screened for the inhibition of CYP2J2, and we discovered a number of marketed drugs as potent and selective CYP2J2 inhibitors. In particular, telmisartan and flunarizine have CYP2J2 inhibition IC(50) values of 0.42 μM and 0.94 μM, respectively, which are at least 10-fold more selective against all other major metabolizing CYPs; moreover, they are not substrates of CYP2J2 and show no time-dependent inhibition toward this CYP. The results of enzyme kinetics studies, supported by molecular modeling, have also elucidated that telmisartan is a mixed-type inhibitor, and flunarizine competitively inhibits CYP2J2. The K(i) for telmisartan is 0.19 μM, with an α value, an indicator of the type of inhibition mechanism, of 2.80, and flunarizine has a K(i) value of 0.13 μM. These newly discovered CYP2J2 inhibitors can be potentially used as a tool to study CYP2J2 in drug metabolism and interaction in a clinical setting.
|
Inhibition of CYP3A4 in human liver microsomes using testosterone substrate by LC-MS/MS method
|
Homo sapiens
|
470.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Discovery and characterization of novel, potent, and selective cytochrome P450 2J2 inhibitors.
Year : 2013
Volume : 41
Issue : 1
First Page : 60
Last Page : 71
Authors : Ren S, Zeng J, Mei Y, Zhang JZ, Yan SF, Fei J, Chen L.
Abstract : Cytochrome P450 (CYP) 2J2 is one of the human CYPs involved in phase I xenobiotics metabolism. It is mainly expressed in extrahepatic tissues, including intestine and cardiovascular systems. The general role of CYP2J2 in drug metabolism is not yet fully understood, and the recent discovery that CYP2J2 can metabolize a wide range of structurally diverse drugs and its primary distribution in the intestine suggest its potentially indispensable role in first-pass intestinal metabolism and involvement in drug-drug interaction. To fully characterize its role in drug metabolism, selective and potent inhibitors of CYP2J2 are necessary tools. In the current study, 69 known drugs were screened for the inhibition of CYP2J2, and we discovered a number of marketed drugs as potent and selective CYP2J2 inhibitors. In particular, telmisartan and flunarizine have CYP2J2 inhibition IC(50) values of 0.42 μM and 0.94 μM, respectively, which are at least 10-fold more selective against all other major metabolizing CYPs; moreover, they are not substrates of CYP2J2 and show no time-dependent inhibition toward this CYP. The results of enzyme kinetics studies, supported by molecular modeling, have also elucidated that telmisartan is a mixed-type inhibitor, and flunarizine competitively inhibits CYP2J2. The K(i) for telmisartan is 0.19 μM, with an α value, an indicator of the type of inhibition mechanism, of 2.80, and flunarizine has a K(i) value of 0.13 μM. These newly discovered CYP2J2 inhibitors can be potentially used as a tool to study CYP2J2 in drug metabolism and interaction in a clinical setting.
|
Inhibition of recombinant CYP3A4 (unknown origin) expressed in baculosomes assessed as decrease in heme level at 10 uM preincubation for 5 mins by LC/UV/MS analysis in presence of 1 mM NADPH
|
Homo sapiens
|
80.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Mechanism-based inactivation of cytochrome P450 3A4 by mibefradil through heme destruction.
Year : 2011
Volume : 39
Issue : 7
First Page : 1188
Last Page : 1195
Authors : Foti RS, Rock DA, Pearson JT, Wahlstrom JL, Wienkers LC.
Abstract : Mibefradil (Posicor) was developed as a calcium channel blocker for the treatment of chronic hypertension. The compound was withdrawn from the market in 1998 because of the potential for rhabdomyolysis, renal failure, or bradycardia when it was coadministered with other drugs. Mibefradil has previously been shown to be a potent reversible (IC(50) = 0.3-2 μM) and mechanism-based (K(i) = 2.3 μM; k(inact) = 0.4 min(-1)) inhibitor of CYP3A4-catalyzed statin metabolism. At present, the mechanism of CYP3A4 inactivation by mibefradil is not known. Mechanism-based inactivation experiments and spectral studies were used to examine the mechanism of CYP3A4 inactivation by mibefradil and its major metabolite, des-methoxyacetyl mibefradil (Ro 40-5966), in vitro. Both mibefradil and Ro 40-5966 were shown to exhibit type I binding characteristics (K(s) = 0.69 ± 0.06 and 1.39 ± 0.04 μM, respectively) toward CYP3A4. Complete K(i)/k(inact) experiments were performed, revealing a rapid and irreversible decrease in CYP3A4-catalyzed 1'-hydroxymidazolam formation. Approximately 70% of CYP3A4 activity was lost in the first minute of incubation with mibefradil, and inactivation was nonlinear after 2 min. Ro 40-5966 also resulted in time-dependent inhibition of CYP3A4, albeit to a lesser extent than mibefradil. The decrease in CYP3A4 activity in the presence of mibefradil and NADPH was subsequently shown to have a good correlation with the time-dependent loss of CO binding, which, coupled with the lack of stable heme and/or apoprotein adducts, suggests heme destruction as the mechanism of inactivation of CYP3A4 by mibefradil.
|
Inhibition of recombinant Cav3.2 channel (unknown origin) expressed in HEK293 cells assessed as effect on calcium flux incubated for 3 mins by FLIPR assay
|
Homo sapiens
|
181.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers.
Year : 2015
Volume : 25
Issue : 18
First Page : 3941
Last Page : 3946
Authors : Renneberg D, Hubler F, Rey M, Hess P, Delahaye S, Gatfield J, Iglarz M, Hilpert K.
Abstract : Chemical evolution of mibefradil resulted in the identification of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers. A SAR study, in vitro and in vivo DMPK properties as well as the in vivo antihypertensive effect in rats are presented.
|
Inhibition of recombinant Cav1.2 channel (unknown origin) expressed in HEK293 cells assessed as effect on calcium flux incubated for 3 mins by FLIPR assay
|
Homo sapiens
|
202.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers.
Year : 2015
Volume : 25
Issue : 18
First Page : 3941
Last Page : 3946
Authors : Renneberg D, Hubler F, Rey M, Hess P, Delahaye S, Gatfield J, Iglarz M, Hilpert K.
Abstract : Chemical evolution of mibefradil resulted in the identification of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers. A SAR study, in vitro and in vivo DMPK properties as well as the in vivo antihypertensive effect in rats are presented.
|
Increase in coronary flow in Wistar rat Langendorff isolated perfused heart
|
Rattus norvegicus
|
26.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers.
Year : 2015
Volume : 25
Issue : 18
First Page : 3941
Last Page : 3946
Authors : Renneberg D, Hubler F, Rey M, Hess P, Delahaye S, Gatfield J, Iglarz M, Hilpert K.
Abstract : Chemical evolution of mibefradil resulted in the identification of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers. A SAR study, in vitro and in vivo DMPK properties as well as the in vivo antihypertensive effect in rats are presented.
|
Inhibition of Cav3.1 (unknown origin)
|
Homo sapiens
|
64.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.
Year : 2017
Volume : 60
Issue : 23
First Page : 9769
Last Page : 9789
Authors : Bezençon O, Heidmann B, Siegrist R, Stamm S, Richard S, Pozzi D, Corminboeuf O, Roch C, Kessler M, Ertel EA, Reymond I, Pfeifer T, de Kanter R, Toeroek-Schafroth M, Moccia LG, Mawet J, Moon R, Rey M, Capeleto B, Fournier E.
Abstract : We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
|
Inhibition of Cav3.2 (unknown origin)
|
Homo sapiens
|
130.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.
Year : 2017
Volume : 60
Issue : 23
First Page : 9769
Last Page : 9789
Authors : Bezençon O, Heidmann B, Siegrist R, Stamm S, Richard S, Pozzi D, Corminboeuf O, Roch C, Kessler M, Ertel EA, Reymond I, Pfeifer T, de Kanter R, Toeroek-Schafroth M, Moccia LG, Mawet J, Moon R, Rey M, Capeleto B, Fournier E.
Abstract : We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
|
Inhibition of Cav3.3 (unknown origin)
|
Homo sapiens
|
130.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.
Year : 2017
Volume : 60
Issue : 23
First Page : 9769
Last Page : 9789
Authors : Bezençon O, Heidmann B, Siegrist R, Stamm S, Richard S, Pozzi D, Corminboeuf O, Roch C, Kessler M, Ertel EA, Reymond I, Pfeifer T, de Kanter R, Toeroek-Schafroth M, Moccia LG, Mawet J, Moon R, Rey M, Capeleto B, Fournier E.
Abstract : We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
|
Inhibition of Cav1.2 (unknown origin)
|
Homo sapiens
|
250.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.
Year : 2017
Volume : 60
Issue : 23
First Page : 9769
Last Page : 9789
Authors : Bezençon O, Heidmann B, Siegrist R, Stamm S, Richard S, Pozzi D, Corminboeuf O, Roch C, Kessler M, Ertel EA, Reymond I, Pfeifer T, de Kanter R, Toeroek-Schafroth M, Moccia LG, Mawet J, Moon R, Rey M, Capeleto B, Fournier E.
Abstract : We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
|
Inhibition of human ERG
|
Homo sapiens
|
580.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.
Year : 2017
Volume : 60
Issue : 23
First Page : 9769
Last Page : 9789
Authors : Bezençon O, Heidmann B, Siegrist R, Stamm S, Richard S, Pozzi D, Corminboeuf O, Roch C, Kessler M, Ertel EA, Reymond I, Pfeifer T, de Kanter R, Toeroek-Schafroth M, Moccia LG, Mawet J, Moon R, Rey M, Capeleto B, Fournier E.
Abstract : We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
|
Inhibition of human heart Nav1.5 expressed in HEK293 cells by whole cell voltage clamp method
|
Homo sapiens
|
500.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.
Year : 2017
Volume : 60
Issue : 23
First Page : 9769
Last Page : 9789
Authors : Bezençon O, Heidmann B, Siegrist R, Stamm S, Richard S, Pozzi D, Corminboeuf O, Roch C, Kessler M, Ertel EA, Reymond I, Pfeifer T, de Kanter R, Toeroek-Schafroth M, Moccia LG, Mawet J, Moon R, Rey M, Capeleto B, Fournier E.
Abstract : We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
|
Inhibition of rat skeletal muscle Nav1.4 expressed in HEK293 cells by whole cell voltage clamp method
|
Rattus norvegicus
|
500.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.
Year : 2017
Volume : 60
Issue : 23
First Page : 9769
Last Page : 9789
Authors : Bezençon O, Heidmann B, Siegrist R, Stamm S, Richard S, Pozzi D, Corminboeuf O, Roch C, Kessler M, Ertel EA, Reymond I, Pfeifer T, de Kanter R, Toeroek-Schafroth M, Moccia LG, Mawet J, Moon R, Rey M, Capeleto B, Fournier E.
Abstract : We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
|
Inhibition of rat brain Nav1.2 expressed in HEK293 cells by whole cell voltage clamp method
|
Rattus norvegicus
|
500.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.
Year : 2017
Volume : 60
Issue : 23
First Page : 9769
Last Page : 9789
Authors : Bezençon O, Heidmann B, Siegrist R, Stamm S, Richard S, Pozzi D, Corminboeuf O, Roch C, Kessler M, Ertel EA, Reymond I, Pfeifer T, de Kanter R, Toeroek-Schafroth M, Moccia LG, Mawet J, Moon R, Rey M, Capeleto B, Fournier E.
Abstract : We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
|
Inhibition of human Nav1.7 expressed in HEK293 cells by whole cell voltage clamp method
|
Homo sapiens
|
500.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.
Year : 2017
Volume : 60
Issue : 23
First Page : 9769
Last Page : 9789
Authors : Bezençon O, Heidmann B, Siegrist R, Stamm S, Richard S, Pozzi D, Corminboeuf O, Roch C, Kessler M, Ertel EA, Reymond I, Pfeifer T, de Kanter R, Toeroek-Schafroth M, Moccia LG, Mawet J, Moon R, Rey M, Capeleto B, Fournier E.
Abstract : We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
|
Inhibition of recombinant human Cav3.1 expressed in HEK293 cells assessed as reduction in KCl-induced increase in intracellular calcium level at 10 uM by fura-2 AM indicator based FDSS assay relative to control
|
Homo sapiens
|
81.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Structural hybridization of pyrrolidine-based T-type calcium channel inhibitors and exploration of their analgesic effects in a neuropathic pain model.
Year : 2019
Volume : 29
Issue : 10
First Page : 1168
Last Page : 1172
Authors : Son WS, Jeong KS, Lim SM, Pae AN.
Abstract : Highly effective and safe drugs for the treatment of neuropathic pain are urgently required and it was shown that blocking T-type calcium channels can be a promising strategy for drug development for neuropathic pain. We have developed pyrrolidine-based T-type calcium channel inhibitors by structural hybridization and subsequent assessment of in vitro activities against Cav3.1 and Cav3.2 channels. Profiling of in vitro ADME properties of compounds was also carried out. The representative compound 17h showed comparable in vivo efficacy to gabapentin in the SNL model, which indicates T-type calcium channel inhibitors can be developed as effective therapeutics for neuropathic pain.
|
Inhibition of Cav3.2 (unknown origin) assessed as reduction in KCl-induced increase in intracellular calcium level at 10 uM by fura-2 AM indicator based FDSS assay relative to control
|
Homo sapiens
|
76.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Structural hybridization of pyrrolidine-based T-type calcium channel inhibitors and exploration of their analgesic effects in a neuropathic pain model.
Year : 2019
Volume : 29
Issue : 10
First Page : 1168
Last Page : 1172
Authors : Son WS, Jeong KS, Lim SM, Pae AN.
Abstract : Highly effective and safe drugs for the treatment of neuropathic pain are urgently required and it was shown that blocking T-type calcium channels can be a promising strategy for drug development for neuropathic pain. We have developed pyrrolidine-based T-type calcium channel inhibitors by structural hybridization and subsequent assessment of in vitro activities against Cav3.1 and Cav3.2 channels. Profiling of in vitro ADME properties of compounds was also carried out. The representative compound 17h showed comparable in vivo efficacy to gabapentin in the SNL model, which indicates T-type calcium channel inhibitors can be developed as effective therapeutics for neuropathic pain.
|
Inhibition of T-type alpha1G channel (unknown origin) expressed in HEK293 cells at 10 uM by fluorescence-based HTS assay
|
Homo sapiens
|
79.2
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 6-pyrazoylamido-3N-substituted azabicyclo[3,1,0]hexane derivatives as T-type calcium channel inhibitors for treatment of neuropathic pain.
Year : 2016
Volume : 24
Issue : 21
First Page : 5028
Last Page : 5035
Authors : Kim JH, Nam G.
Abstract : A new series of aryls, including benzo[d]imidazole/isoxazole/pyrazole, conjugated to 3N-substituted-azabicyclo[3.1.0]hexane derivatives were designed and synthesized as inhibitors of T-type calcium channels. Among the synthesized compounds, 3N-R-substituted azabicyclo[3.1.0]hexane carboxamide derivatives containing 5-isobutyl-1-phenyl-pyrazole ring exhibited potent and selective T-channel inhibition and good metabolic stability without CYP450 inhibition. Compounds 10d and 10e contained hydrophobic substituents at the 3N-position and exhibited potent in vitro efficacy, as well as neuropathic pain alleviation in rats.
|
Inhibition of T-type alpha1H channel (unknown origin) expressed in HEK293 cells at 10 uM by fluorescence-based HTS assay
|
Homo sapiens
|
76.0
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 6-pyrazoylamido-3N-substituted azabicyclo[3,1,0]hexane derivatives as T-type calcium channel inhibitors for treatment of neuropathic pain.
Year : 2016
Volume : 24
Issue : 21
First Page : 5028
Last Page : 5035
Authors : Kim JH, Nam G.
Abstract : A new series of aryls, including benzo[d]imidazole/isoxazole/pyrazole, conjugated to 3N-substituted-azabicyclo[3.1.0]hexane derivatives were designed and synthesized as inhibitors of T-type calcium channels. Among the synthesized compounds, 3N-R-substituted azabicyclo[3.1.0]hexane carboxamide derivatives containing 5-isobutyl-1-phenyl-pyrazole ring exhibited potent and selective T-channel inhibition and good metabolic stability without CYP450 inhibition. Compounds 10d and 10e contained hydrophobic substituents at the 3N-position and exhibited potent in vitro efficacy, as well as neuropathic pain alleviation in rats.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-6.34
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
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Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.43
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.43
%
|
|
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.
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Inhibition of human Cav3.1 expressed in tsA-201 cells at 10uM by patch clamp electrophysiology
|
Homo sapiens
|
95.9
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and cytotoxic effects of 2-thio-3,4-dihydroquinazoline derivatives as novel T-type calcium channel blockers.
Year : 2020
Volume : 28
Issue : 11
First Page : 115491
Last Page : 115491
Authors : Nam Y, Ryu KD, Jang C, Moon YH, Kim M, Ko D, Chung KS, Gandini MA, Lee KT, Zamponi GW, Lee JY.
Abstract : In our previous work, a series of 2-amino-3,4-dihydroquinazoline derivativesusing an electron acceptor group was reported to be potent T-type calcium channel blockers and exhibit strong cytotoxic effects against various cancerous cell lines. To investigate the role of the guanidine moiety in the 2-amino-3,4-dihydroquinazoline scaffold as a pharmacophore for dual biological activity, a new series of 2-thio-3,4-dihydroquniazoline derivatives using an electron donor group at the C2-position was synthesized and evaluated for T-type calcium channel blocking activity and cytotoxic effects against two human cancerous cell lines (lung cancer A549 and colon cancer HCT-116). Among them, compound 6g showed potent inhibition of Ca<sub>v</sub>3.2 currents (83% inhibition) at 10 µM concentrations. The compound also exhibited IC<sub>50</sub> values of 5.0 and 6.4 µM against A549 and HCT-116 cell lines, respectively, which are comparable to the parental lead compound KYS05090. These results indicate that the isothiourea moiety similar to the guanidine moiety of 2-amino-3,4-dihydroquinazoline derivatives may be an essential pharmacophore for the desired biological activities. Therefore, our preliminary work can provide the opportunity to expand a chemical repertoire to improve affinity and selectivity for T-type calcium channels.
