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2.
J Med Chem ; 50(5): 1050-7, 2007 Mar 08.
Article in English | MEDLINE | ID: mdl-17274609

ABSTRACT

The synthesis of a series of 3-beta-hydroxyethyl-4-arylquinolin-2-ones is described. These compounds contain hydrophilic and hydrophobic substituents ortho to the phenolic OH in the C ring of the quinolinone. Electrophysiological evaluation of the panel of compounds revealed that 11 and 16 with an unbranched ortho substituent retain activity as maxi-K ion channel openers. Members of this series of compounds can exist as stable atropisomers. Calculated estimates of the energy barrier for rotation around the aryl-aryl single bond in 3 is 31 kcal/mol. The atropisomers of (+/-)-3, (+/-)-4, and (+/-)-11 were separated by chiral HPLC and tested for their effect on maxi-K mediated outward current in hSlo injected X. laevis oocytes. The (-) isomer in each case was found to be more active than the corresponding (+) isomer, suggesting that the ion channel exhibits stereoselective activation. X-ray crystallographic structures of (+)-3 and (+)-11 were determined. Evaluation of the stability of (-)-3 at 80 degrees C in n-butanol indicated a 19.6% conversion to (+)-3 over 72 h. In human serum at 37 degrees C (-)-3 did not racemize over the course of the 30 h study.


Subject(s)
Large-Conductance Calcium-Activated Potassium Channels/drug effects , Quinolines/chemical synthesis , Animals , Crystallography, X-Ray , Female , Humans , In Vitro Techniques , Ion Channel Gating , Large-Conductance Calcium-Activated Potassium Channels/physiology , Molecular Structure , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Quinolines/chemistry , Quinolines/pharmacology , Stereoisomerism , Thermodynamics , Xenopus laevis
3.
J Med Chem ; 50(3): 528-42, 2007 Feb 08.
Article in English | MEDLINE | ID: mdl-17266205

ABSTRACT

Compound 8a (BMS-191011), an opener of the cloned large-conductance, Ca2+-activated potassium (maxi-K) channel, demonstrated efficacy in in vivo stroke models, which led to its nomination as a candidate for clinical evaluation. Its maxi-K channel opening properties were consistent with its structural topology, being derived by combining elements from other known maxi-K openers. However, 8a suffered from poor aqueous solubility, which complicated elucidation of SAR during in vitro evaluation. The activity of 8a in in vivo stroke models and studies directed toward improving its solubility are reported herein. Enhanced solubility was achieved by appending heterocycles to the 8a scaffold, and a notable observation was made that inclusion of a simple amino group (anilines 8k and 8l) yielded excellent in vitro maxi-K ion channel opening activity and enhanced brain-to-plasma partitioning compared to the appended heterocycles.


Subject(s)
Large-Conductance Calcium-Activated Potassium Channels/physiology , Oxadiazoles/pharmacology , Animals , Brain/metabolism , Crystallography, X-Ray , Female , In Vitro Techniques , Ion Channel Gating , Molecular Structure , Oocytes/drug effects , Oocytes/physiology , Oxadiazoles/chemistry , Oxadiazoles/pharmacokinetics , Patch-Clamp Techniques , Plasma , Rats , Rats, Inbred SHR , Solubility , Stroke/drug therapy , Stroke/pathology , Structure-Activity Relationship , Xenopus laevis
4.
Neuropharmacology ; 51(4): 896-906, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16876206

ABSTRACT

The Slack (Sequence like a calcium-activated K channel) (Slo2.2) gene is abundantly expressed in the mammalian brain and encodes a sodium-activated K+ (KNa) channel. Although the specific roles of Slack channel subunits in neurons remain to be identified, they may play a role in the adaptation of firing rate and in protection against ischemic injury. In the present study, we have generated a stable cell line expressing the Slack channel, and have analyzed the pharmacological properties of these channels in these cells and in Xenopus oocytes. Two known blockers of KNa channels, bepridil and quinidine, inhibited Slack currents in a concentration-dependent manner and decreased channel activity in excised membrane patches. The inhibition by bepridil was potent, with an IC50 of 1.0 microM for inhibition of Slack currents in HEK cells. In contrast, bithionol was found to be a robust activator of Slack currents. When applied to the extracellular face of excised patches, bithionol rapidly induced a reversible increase in channel opening, suggesting that it acts on Slack channels relatively directly. These data establish an important early characterization of agents that modulate Slack channels, a process essential for the experimental manipulation of Slack currents in neurons.


Subject(s)
Potassium Channels, Calcium-Activated/physiology , Animals , Anti-Infective Agents, Local/pharmacology , Bepridil/pharmacology , Bithionol/pharmacology , Calcium Channel Blockers/pharmacology , Cell Line, Transformed , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Electric Stimulation/methods , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Potentials/radiation effects , Oocytes , Patch-Clamp Techniques/methods , Potassium Channels, Calcium-Activated/genetics , Quinidine/pharmacology , Transfection , Xenopus
5.
Bioorg Med Chem Lett ; 15(19): 4286-90, 2005 Oct 01.
Article in English | MEDLINE | ID: mdl-16061379

ABSTRACT

Quinolinone 1 is a potent maxi-K potassium channel opener. In an effort to design analogs of 1 with a better inhibitory profile toward the CYP2C9 isozyme, the two acidic sites were chemically modified independently to generate a number of analogs. These analogs were evaluated as maxi-K channel openers in vitro using Xenopus laevis oocytes expressing cloned hSlo maxi-K channels. Compounds 15, 17, and 19 showed potent activity as maxi-K channel openers and were further evaluated for inhibition of the activity of the CYP2C9 isozyme. Compounds 17 and 19 showed diminished inhibitory potency against 2C9 and also against a panel of other more common CYP isozymes.


Subject(s)
Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Quinolones/chemical synthesis , Animals , Binding Sites , Cytochrome P-450 CYP2C9 , Cytochrome P-450 Enzyme Inhibitors , Humans , Inhibitory Concentration 50 , Isoenzymes/antagonists & inhibitors , Oocytes , Quinolones/pharmacology , Structure-Activity Relationship , Xenopus laevis
6.
Bioorg Med Chem Lett ; 14(17): 4479-82, 2004 Sep 06.
Article in English | MEDLINE | ID: mdl-15357975

ABSTRACT

A novel series of 4-aryl-3-(mercapto)quinolin-2-one derivatives was prepared and evaluated as openers of the cloned maxi-K channel hSlo expressed in Xenopus laevis oocytes by utilizing electrophysiological methods. The effect of these maxi-K openers on corporal smooth muscle was studied in vitro using isolated rabbit corpus cavernosum. In vivo efficacy has been demonstrated with a selective maxi-K opening relaxant in a rat model of erectile function.


Subject(s)
Muscle, Smooth, Vascular/drug effects , Penis/drug effects , Potassium Channels, Calcium-Activated/physiology , Quinolones/chemistry , Vasodilation/drug effects , Animals , Female , In Vitro Techniques , Large-Conductance Calcium-Activated Potassium Channels , Male , Muscle, Smooth, Vascular/physiology , Penis/physiology , Quinolones/pharmacology , Rabbits , Rats , Rats, Inbred F344 , Vasodilation/physiology , Xenopus laevis
7.
Bioorg Med Chem Lett ; 14(17): 4533-7, 2004 Sep 06.
Article in English | MEDLINE | ID: mdl-15357987

ABSTRACT

Bioisosteric replacement studies led to the identification of N-(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide ((S)-3) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)-N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide ((S)-4), and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-5) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 microM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (+/-)-3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds (S)-4 and (S)-5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.


Subject(s)
Acrylamides/chemistry , Benzofurans/chemistry , Potassium Channels, Voltage-Gated/metabolism , Acrylamides/pharmacology , Animals , Benzofurans/pharmacology , Cell Line , Dose-Response Relationship, Drug , Hippocampus/drug effects , Hippocampus/metabolism , Humans , KCNQ2 Potassium Channel , Rats
8.
Bioorg Med Chem Lett ; 14(20): 5089-93, 2004 Oct 18.
Article in English | MEDLINE | ID: mdl-15380205

ABSTRACT

A series of Maxi-K openers for the treatment of erectile dysfunction based on the 3-thio-quinolinone core is described. Significant levels of channel opening (up to 550% of control) are seen in transfected oocytes. Functional activity in rabbit corpus cavernosum tissue strips confirms the potential to effect therapy for ED, the effect being maximal for the 3-amino-2-hydroxy thiol side chain.


Subject(s)
Ion Channel Gating , Penile Erection/drug effects , Potassium Channels, Calcium-Activated/drug effects , Quinolines/chemical synthesis , Sulfides/chemical synthesis , Vasodilator Agents/chemical synthesis , Animals , Erectile Dysfunction/drug therapy , Humans , In Vitro Techniques , Large-Conductance Calcium-Activated Potassium Channels , Male , Muscle Relaxation/drug effects , Muscle Relaxation/physiology , Muscle, Smooth, Vascular/drug effects , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Penile Erection/physiology , Penis/blood supply , Quinolines/chemistry , Quinolines/pharmacology , Rabbits , Structure-Activity Relationship , Sulfides/chemistry , Sulfides/pharmacology , Vasodilator Agents/chemistry , Vasodilator Agents/pharmacology
9.
J Med Chem ; 47(11): 2887-96, 2004 May 20.
Article in English | MEDLINE | ID: mdl-15139767

ABSTRACT

A new class of acrylamides was synthesized, and the effects of these analogues on outward potassium current were evaluated by using two electrode voltage clamp recordings from Xenopus laevis oocytes expressing cloned mKCNQ2 channels. SAR studies indicated that the pharmacophore of the acrylamide series includes the (S) absolute configuration at the (1-phenyl)ethyl moiety and the alpha,beta-unsaturated acrylamide functionality with a free NH. This study identified (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide ((S)-1) and (S)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-fluoro-phenyl)-acrylamide ((S)-2) as KCNQ2 openers for further electrophysiological evaluations. These two acrylamides demonstrated significant activity in the cortical spreading depression model of migraine as we reported previously.


Subject(s)
Acrylamides/chemical synthesis , Cinnamates/chemical synthesis , Morpholines/chemical synthesis , Potassium Channels/drug effects , Acrylamides/chemistry , Acrylamides/pharmacology , Animals , Cinnamates/chemistry , Cinnamates/pharmacology , Cortical Spreading Depression/drug effects , Humans , KCNQ2 Potassium Channel , Mice , Morpholines/chemistry , Morpholines/pharmacology , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Potassium Channels/physiology , Potassium Channels, Voltage-Gated , Stereoisomerism , Structure-Activity Relationship , Xenopus laevis
10.
Bioorg Med Chem Lett ; 14(8): 1991-5, 2004 Apr 19.
Article in English | MEDLINE | ID: mdl-15050644

ABSTRACT

(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-2) was identified as a potent and efficacious KCNQ2 opener. This compound demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices, and the inhibition mediated by (S)-2 was reversed by the KCNQ blocker linopirdine.


Subject(s)
Acrylamides/pharmacology , Hippocampus/drug effects , Neurons/drug effects , Oxazines/pharmacology , Potassium Channels/drug effects , Acrylamides/chemical synthesis , Animals , Dose-Response Relationship, Drug , Hippocampus/metabolism , Hippocampus/pathology , Humans , KCNQ2 Potassium Channel , Kidney/cytology , Kidney/drug effects , Kidney/metabolism , Mice , Molecular Structure , Neurons/metabolism , Neurons/pathology , Oxazines/chemical synthesis , Patch-Clamp Techniques , Potassium Channels/genetics , Potassium Channels/metabolism , Potassium Channels, Voltage-Gated , Rats , Structure-Activity Relationship
11.
Bioorg Med Chem Lett ; 14(7): 1615-8, 2004 Apr 05.
Article in English | MEDLINE | ID: mdl-15026035

ABSTRACT

3-amino-4-benzylquinolin-2-ones have been identified as a novel class of KCNQ2 channel openers. Synthesis and SAR is described along with their electrophysiological evaluation as activators of the cloned mKCNQ2 channel expressed in Xenopus laevis oocytes. The preliminary SAR data suggest the importance of both the trifluoromethylsulfonamido group and electron-withdrawing substituents on the quinolone nucleus for expression of KCNQ2 channel opening properties.


Subject(s)
Potassium Channels/physiology , Quinolones/chemical synthesis , Quinolones/pharmacology , Animals , Female , Ion Channel Gating/drug effects , Ion Channel Gating/physiology , KCNQ2 Potassium Channel , Potassium Channels/agonists , Potassium Channels, Voltage-Gated , Structure-Activity Relationship , Xenopus laevis
12.
J Med Chem ; 46(15): 3197-200, 2003 Jul 17.
Article in English | MEDLINE | ID: mdl-12852750
13.
J Med Chem ; 46(14): 2819-22, 2003 Jul 03.
Article in English | MEDLINE | ID: mdl-12825925

ABSTRACT

Novel 4-aryl-3-(hydroxyalkyl)quinoline-2-one derivatives were prepared and evaluated as openers of the cloned maxi-K channel hSlo expressed in Xenopus laevis oocytes by utilizing electrophysiological methods. The effect of these maxi-K openers on corporal smooth muscle was studied in vitro using isolated rabbit corpus cavernosum. From this study, a potent maxi-K opener was identified as an effective relaxant of rabbit corporal smooth muscle and shown to be active in an in vivo animal model of male erectile function.


Subject(s)
Muscle, Smooth/drug effects , Penis/drug effects , Potassium Channels, Calcium-Activated/drug effects , Quinolones/chemical synthesis , Animals , Blood Pressure/drug effects , Electric Stimulation , Erectile Dysfunction/drug therapy , In Vitro Techniques , Large-Conductance Calcium-Activated Potassium Channels , Male , Muscle Relaxation/drug effects , Muscle, Smooth/physiology , Penile Erection/drug effects , Penis/innervation , Penis/physiology , Pressure , Quinolones/chemistry , Quinolones/pharmacology , Rabbits , Rats , Rats, Inbred F344 , Structure-Activity Relationship
16.
J Med Chem ; 45(14): 2942-52, 2002 Jul 04.
Article in English | MEDLINE | ID: mdl-12086481

ABSTRACT

A series of diphenyl-substituted heterocycles were synthesized and evaluated by electrophysiological techniques as openers of the cloned mammalian large-conductance, Ca(2+)-activated potassium (maxi-K) channel. The series was designed from deannulation of known benzimidazolone maxi-K opener NS-004 (2) thereby providing an effective template for obtaining structure-activity-related information. The triazolone ring system was the most studied wherein 4,5-diphenyltriazol-3-one 6d (maxi-K = 158%) was identified as the optimal maxi-K channel opener.


Subject(s)
Potassium Channels, Calcium-Activated/agonists , Triazoles/chemical synthesis , Animals , Crystallography, X-Ray , In Vitro Techniques , Large-Conductance Calcium-Activated Potassium Channels , Models, Molecular , Molecular Conformation , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Potassium Channels, Calcium-Activated/physiology , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology , Xenopus laevis
18.
Bioorg Med Chem Lett ; 12(7): 1117-20, 2002 Apr 08.
Article in English | MEDLINE | ID: mdl-11909730

ABSTRACT

A series of 1,3-diaryl 1,2,4-(4H)-triazol-5-ones was prepared and shown by electrophysiological analysis to activate a cloned maxi-K channel mSlo (or hSlo) expressed in Xenopus laevis oocytes. The effects of these structurally novel maxi-K channel openers on bladder contractile function were studied in vitro using isolated rat bladder strips pre-contracted with carbachol. Several 1,3-diaryl 1,2,4-(4H)-triazol-5-one derivatives were found to be potent smooth muscle relaxants but this activity did not completely correlate with maxi-K channel opening.


Subject(s)
Azo Compounds/chemical synthesis , Azo Compounds/pharmacology , Oocytes/drug effects , Oocytes/physiology , Potassium Channels, Calcium-Activated/drug effects , Urinary Incontinence/drug therapy , Animals , Calcium/metabolism , Carbachol/pharmacology , Cells, Cultured/drug effects , Electrophysiology , Humans , Large-Conductance Calcium-Activated Potassium Channels , Male , Mice , Microinjections , Models, Molecular , Muscle Relaxation/drug effects , Muscle, Smooth/physiology , Potassium Channels, Calcium-Activated/genetics , Potassium Channels, Calcium-Activated/metabolism , RNA, Messenger/metabolism , Rats , Structure-Activity Relationship , Urinary Bladder/metabolism , Xenopus laevis
19.
J Med Chem ; 45(7): 1487-99, 2002 Mar 28.
Article in English | MEDLINE | ID: mdl-11906290

ABSTRACT

A series of 3-aryloxindole derivatives were synthesized and evaluated as activators of the cloned maxi-K channel mSlo expressed in Xenopus laevis oocytes using electrophysiological methods. The most promising maxi-K openers to emerge from this study were (+/-)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one ((+/-)-8c) and its 3-des-hydroxy analogue (+/-)-11b. The individual enantiomers of (+/-)-8c were synthesized, and the maxi-K channel-opening properties were shown to depend on the absolute configuration of the single stereogenic center with the efficacy of (-)-8c superior to that of both (+)-8c and the racemic mixture when evaluated at a concentration of 20 microM. Racemic 11b exhibited greater efficacy than either the racemic 8c or the more active enantiomer in the electrophysiological evaluation. In vitro metabolic stability studies conducted with (+/-)-8c and (+/-)-11b in rat liver S9 microsomal fractions revealed significant oxidative degradation with two hydroxylated metabolites observed by liquid chromatography/mass spectrometry for each compound in addition to the production of 8c from 11b. The pharmacokinetic properties of (+/-)-8c and (+/-)-11b were determined in rats as a prelude to evaluation in a rat model of stroke that involved permanent occlusion of the middle cerebral artery (MCAO model). In the MCAO model, conducted in the spontaneously hypertensive rat, the more polar 3-hydroxy derivative (+/-)-8c did not demonstrate a significant reduction in cortical infarct volume when administered intravenously at doses ranging from 0.1 to 10 mg/kg as a single bolus 2 h after middle cerebral artery occlusion when compared to vehicle-treated controls. In contrast, intravenous administration of (+/-)-11b at a dose of 0.03 mg/kg was found to reduce the measured cortical infarct volume by approximately 18% when compared to vehicle-treated control animals. Intraperitoneal administration of (+/-)-11b at a dose of 10 mg/kg 2 h following artery occlusion was shown to reduce infarct volume by 26% when compared to vehicle-treated controls. To further probe the effects of compounds (+/-)-8c and (+/-)-11b on neurotransmitter release in vitro, both compounds were examined for their ability to reduce electrically stimulated [3H]-glutamate release from rat hippocampal slices that had been preloaded with [3H]-glutamate. Only (+/-)-11b was able to demonstrate a significant inhibition [3H]-glutamate release in this assay at a concentration of 20 microM, providing concordance with the profile of these compounds in the MCAO model. Although (+/-)-11b showed some promise as a potential developmental candidate for the treatment of the sequelae of stroke based on its efficacy in the rat MCAO model, the pharmacokinetic profile of this compound was considered to be less than optimal and was not pursued in favor of derivatives with enhanced metabolic stability.


Subject(s)
Calcium/chemistry , Indoles/chemistry , Indoles/pharmacology , Neurons/drug effects , Potassium Channels, Calcium-Activated/chemistry , Animals , COS Cells , Calcium/metabolism , Cerebral Arteries/metabolism , Dose-Response Relationship, Drug , Electrophysiology , Glutamic Acid/chemistry , Hippocampus/drug effects , Large-Conductance Calcium-Activated Potassium Channels , Male , Models, Chemical , Models, Molecular , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Protein Binding , Protein Structure, Tertiary , Rats , Rats, Inbred SHR , Rats, Sprague-Dawley , Structure-Activity Relationship , Temperature , Xenopus , Xenopus laevis
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