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1.
ACS Med Chem Lett ; 15(4): 524-532, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38628784

RESUMO

Eleven-nineteen leukemia (ENL) is an epigenetic reader protein that drives oncogenic transcriptional programs in acute myeloid leukemia (AML). AML is one of the deadliest hematopoietic malignancies, with an overall 5-year survival rate of 27%. The epigenetic reader activity of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl marks on histone tails and colocalizes with promoters of actively transcribed genes that are essential for leukemia. Prior to the discovery of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and is appropriate for in vivo evaluation of the ENL YEATS inhibition mechanism in AML.

2.
Antimicrob Agents Chemother ; 56(8): 4161-7, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22615282

RESUMO

HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.


Assuntos
Hepacivirus/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Quinoxalinas/farmacologia , Quinoxalinas/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Amidas , Animais , Antivirais/farmacologia , Carbamatos , Ciclopropanos , Cães , Farmacorresistência Viral , Genótipo , Hepacivirus/enzimologia , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Fígado/efeitos dos fármacos , Pan troglodytes , Quinoxalinas/metabolismo , Ratos , Sulfonamidas , Carga Viral/efeitos dos fármacos
3.
Bioorg Med Chem Lett ; 22(23): 7201-6, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23021993

RESUMO

A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Hepacivirus/enzimologia , Compostos Macrocíclicos/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Proteínas de Transporte/metabolismo , Ciclização , Genótipo , Meia-Vida , Hepacivirus/genética , Peptídeos e Proteínas de Sinalização Intracelular , Cinética , Fígado/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacocinética , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Quinolinas/química , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo
4.
Bioorg Med Chem Lett ; 22(23): 7207-13, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23084906

RESUMO

A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Hepacivirus/enzimologia , Compostos Macrocíclicos/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Sítios de Ligação , Proteínas de Transporte/metabolismo , Domínio Catalítico , Ciclização , Genótipo , Meia-Vida , Hepacivirus/genética , Peptídeos e Proteínas de Sinalização Intracelular , Cinética , Fígado/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacocinética , Simulação de Acoplamento Molecular , Mutação , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo
5.
J Med Chem ; 65(22): 15208-15226, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36346696

RESUMO

Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.


Assuntos
Adenilil Ciclases , Motilidade dos Espermatozoides , Animais , Masculino , Adenilil Ciclases/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Oócitos/metabolismo , Transdução de Sinais/fisiologia , Motilidade dos Espermatozoides/efeitos dos fármacos , Anticoncepcionais Masculinos/química , Anticoncepcionais Masculinos/farmacologia
6.
ACS Med Chem Lett ; 12(8): 1283-1287, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34413957

RESUMO

Soluble adenylyl cyclase (sAC) has gained attention as a potential therapeutic target given the role of this enzyme in intracellular signaling. We describe successful efforts to design improved sAC inhibitors amenable for in vivo interrogation of sAC inhibition to assess its potential therapeutic applications. This work culminated in the identification of TDI-10229 (12), which displays nanomolar inhibition of sAC in both biochemical and cellular assays and exhibits mouse pharmacokinetic properties sufficient to warrant its use as an in vivo tool compound.

7.
Antimicrob Agents Chemother ; 54(1): 305-11, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19841155

RESUMO

The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Indóis/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Área Sob a Curva , Linhagem Celular , Ciclopropanos , Cães , Genótipo , Meia-Vida , Hepacivirus/enzimologia , Hepacivirus/genética , Humanos , Indóis/farmacocinética , Interferon alfa-2 , Interferon-alfa/farmacologia , Isoindóis , Lactamas Macrocíclicas , Leucina/análogos & derivados , Macaca mulatta , Pan troglodytes , Prolina/análogos & derivados , Inibidores de Proteases/farmacocinética , Ratos , Proteínas Recombinantes , Replicon , Especificidade por Substrato , Sulfonamidas , Proteínas não Estruturais Virais/genética
9.
Bioorg Med Chem Lett ; 19(9): 2574-8, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19328685

RESUMO

HCV-NS3 protease is essential for viral replication and NS3 protease inhibitors have shown proof of concept in clinical trials. Novel P2-P4 macrocycle inhibitors of NS3/4A comprising a P1 C-terminal carboxylic acid have recently been disclosed. A series of analogs, in which the carboxylic residue is replaced by phosphorous acid functionalities were synthesized and found to be inhibitors of the NS3 protease. Among them the methylphosphinate analogue showed nanomolar level of enzyme inhibition and sub-micromolar potency in the replication assay.


Assuntos
Antivirais/síntese química , Química Farmacêutica/métodos , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hepatite C/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Fosfatos/química , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química
10.
Bioorg Med Chem Lett ; 19(17): 5132-5, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19648007

RESUMO

A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure-activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K(+) channel. Preferred compounds were subsequently evaluated for selectivity in an alpha(1)-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.


Assuntos
Benzocicloeptenos/síntese química , Neurotransmissores/síntese química , Piridinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Benzocicloeptenos/química , Benzocicloeptenos/farmacologia , Linhagem Celular , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Neurotransmissores/química , Neurotransmissores/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade
11.
J Am Chem Soc ; 130(14): 4607-9, 2008 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-18338894

RESUMO

Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.


Assuntos
Hepacivirus/enzimologia , Compostos Macrocíclicos/química , Inibidores de Serina Proteinase/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Modelos Moleculares , Ratos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Proteínas não Estruturais Virais/química
12.
J Pharmacol Exp Ther ; 324(1): 322-30, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17967939

RESUMO

Drug discovery efforts have focused recently on atrial-selective targets, including the Kv1.5 channel, which underlies the ultrarapid delayed rectifier current, I(Kur), to develop novel treatments for atrial fibrillation (AF). Two structurally distinct compounds, a triarylethanolamine TAEA and an isoquinolinone 3-[(dimethylamino)-methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (ISQ-1), blocked I(Kur) in Chinese hamster ovary cells expressing human Kv1.5 with IC(50) values of 238 and 324 nM, respectively. In anesthetized dogs, i.v. infusions of TAEA and ISQ-1 elicited comparable 16% increases in atrial refractory period, with no effect on ventricular refractory period or QTc interval. Plasma concentrations at end infusion for TAEA and ISQ-1 were 58.5 +/- 23.6 and 330.3 +/- 43.5 nM, respectively. The abilities of TAEA and ISQ-1 to terminate AF, with comparison to the rapidly activating component of delayed rectifier potassium current blocker (+)-N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2,4'-piperidin)-6-yl]methanesulfonamide] monohydrochloride (MK-499) and the class IC 1-[2-[2-hydroxy-3-(propylamino)-propoxy]phenyl]-3-phenyl-1-propanone (propafenone), were assessed in conscious dogs with heart failure and inducible AF (entry criterion). All test agents administered in i.v. bolus regimens terminated AF in at least half of animals tested; conversely no agent was universally effective. MK-499, ISQ-1, TAEA, and propafenone terminated AF in five of six, four of seven, four of six, and five of six animals at plasma concentrations of 32.6 +/- 18.7, 817 +/- 274, 714 +/- 622, and 816 +/- 240 nM, respectively. Directed cardiac electrophysiologic studies in anesthetized dogs using i.v. bolus (consistent with AF studies) plus infusion regimens with TAEA and ISQ-1 demonstrated significant increases in atrial refractory period (12-15%), A-H and P-A intervals, but no effects on ventricular refractory period, H-V, and HEG intervals. The demonstration of AF termination with TAEA and ISQ-1 in the dog heart failure model extends the profile of antiarrhythmic efficacy of Kv1.5 blockade.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Isoquinolinas/uso terapêutico , Canal de Potássio Kv1.5/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/uso terapêutico , Piridinas/uso terapêutico , Animais , Fibrilação Atrial/fisiopatologia , Benzopiranos/uso terapêutico , Linhagem Celular , Cães , Feminino , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Humanos , Masculino , Piperidinas/uso terapêutico , Propafenona/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico
13.
J Med Chem ; 50(4): 807-19, 2007 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-17249648

RESUMO

The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.


Assuntos
Analgésicos/síntese química , Encéfalo/metabolismo , Pirimidinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Antiparkinsonianos/síntese química , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cães , Feminino , Lobo Frontal/metabolismo , Humanos , Masculino , Medição da Dor , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
14.
J Med Chem ; 49(24): 6954-7, 2006 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-17125248

RESUMO

Novel 3-cyanoisoquinoline Kv1.5 antagonists have been prepared and evaluated in in vitro and in vivo assays for inhibition of the Kv1.5 potassium channel and its associated cardiac potassium current, IKur. Structural modifications of isoquinolinone lead 1 afforded compounds with excellent potency, selectivity, and oral bioavailability.


Assuntos
Antiarrítmicos/síntese química , Fibrilação Atrial/tratamento farmacológico , Isoquinolinas/síntese química , Canal de Potássio Kv1.5/antagonistas & inibidores , Nitrilas/síntese química , Administração Oral , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Disponibilidade Biológica , Eletrofisiologia , Coração/efeitos dos fármacos , Coração/fisiologia , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Canal de Potássio Kv1.5/fisiologia , Nitrilas/química , Nitrilas/farmacologia , Técnicas de Patch-Clamp , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
15.
Pharmacol Res Perspect ; 3(6): e00198, 2015 12.
Artigo em Inglês | MEDLINE | ID: mdl-27022470

RESUMO

The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (K i, 8.1 nmol L(-1)) specific to GluN2B with an IC 50 of 3.6 nmol L(-1) and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED 50) of 0.3-0.7 mg kg(-1) (RO, 30-50%); increase in locomotor activity was observed at ED 50 of 2 mg kg(-1), corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L(-1), similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L(-1), respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with T max of ~1 h and t 1/2 of 12-17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.

16.
ChemMedChem ; 10(4): 727-35, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25759009

RESUMO

With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.


Assuntos
Antivirais/farmacologia , Hepacivirus/enzimologia , Compostos Macrocíclicos/farmacologia , Quinazolinonas/farmacologia , Sulfonas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Cristalografia por Raios X , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Modelos Moleculares , Mutação , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Sulfonas/farmacocinética , Proteínas não Estruturais Virais/genética
17.
J Med Chem ; 47(8): 2089-96, 2004 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-15056006

RESUMO

Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.


Assuntos
Analgésicos/síntese química , Benzimidazóis/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Encéfalo/metabolismo , Cálcio/metabolismo , Carragenina , Linhagem Celular , Cães , Feminino , Humanos , Hiperalgesia/sangue , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Técnicas In Vitro , Masculino , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologia , Relação Estrutura-Atividade
18.
J Neurosci Methods ; 137(2): 247-55, 2004 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-15262068

RESUMO

To facilitate the discovery of novel N-methyl-d-aspartate (NMDA) receptor antagonists, we have developed a high-throughput functional assay based on fluorescence detection of free intracellular calcium concentrations. Mouse fibroblast L(tk-) cells expressing human NR1a/NR2B NMDA receptors were plated in 96-well plates and loaded with fluorescence calcium indicator fluo-3 AM. NR2B antagonists were added after stimulation of NMDA receptors with 10 microM glutamate and 10 microM glycine. Changes in fluorescence after the addition of the antagonists were fitted by a single exponential equation providing k(obs). The concentration dependence of k(obs) was linear for all NR2B antagonists at concentrations where k(obs) < 0.2 s(-1). The values of k(obs) for six structurally distinct NR2B antagonists were in the range of 1.1 to 7.5 x 10(5) M(-1)s(-1). These values were several orders of magnitude slower than that obtained for diffusion limited Mg(2+) channel block. The rate constants k(off) provided the values of t(1/2) for dissociation of NR2B antagonists in the range of 1.8 min for ifenprodil to 240 min for the slowest novel antagonist. The IC(50) values obtained from the end-point fluorescence measurements agree with K(d) values calculated from kinetic measurements. All kinetic constants, obtained using our fluorescence method, correlate well with data measured by voltage clamp.


Assuntos
Cálcio/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Técnicas de Patch-Clamp/métodos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Espectrometria de Fluorescência/métodos , Compostos de Anilina/metabolismo , Animais , Linhagem Celular/efeitos dos fármacos , Linhagem Celular/fisiologia , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/química , Corantes Fluorescentes/metabolismo , Humanos , Cinética , Camundongos , Modelos Neurológicos , Piperidinas/farmacologia , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/genética , Fatores de Tempo , Transfecção/métodos , Xantenos/metabolismo
19.
ACS Med Chem Lett ; 5(3): 264-9, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900818

RESUMO

We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.

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