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1.
J Med Chem ; 66(18): 13205-13246, 2023 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-37712656

RESUMO

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.

2.
J Med Chem ; 65(18): 12445-12459, 2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36098485

RESUMO

Huntington's disease (HD) is a lethal autosomal dominant neurodegenerative disorder resulting from a CAG repeat expansion in the huntingtin (HTT) gene. The product of translation of this gene is a highly aggregation-prone protein containing a polyglutamine tract >35 repeats (mHTT) that has been shown to colocalize with histone deacetylase 4 (HDAC4) in cytoplasmic inclusions in HD mouse models. Genetic reduction of HDAC4 in an HD mouse model resulted in delayed aggregation of mHTT, along with amelioration of neurological phenotypes and extended lifespan. To further investigate the role of HDAC4 in cellular models of HD, we have developed bifunctional degraders of the protein and report the first potent and selective degraders of HDAC4 that show an effect in multiple cell lines, including HD mouse model-derived cortical neurons. These degraders act via the ubiquitin-proteasomal pathway and selectively degrade HDAC4 over other class IIa HDAC isoforms (HDAC5, HDAC7, and HDAC9).


Assuntos
Histona Desacetilases , Doença de Huntington , Animais , Modelos Animais de Doenças , Desenvolvimento de Medicamentos , Histona Desacetilases/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Camundongos , Neurônios/metabolismo , Proteólise , Ubiquitinas
3.
Biochem Biophys Res Commun ; 521(3): 549-554, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31677786

RESUMO

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of a CAG triplet repeat (encoding for a polyglutamine tract) within the first exon of the huntingtin gene. Expression of the mutant huntingtin (mHTT) protein can result in the production of N-terminal fragments with a robust propensity to form oligomers and aggregates, which may be causally associated with HD pathology. Several lines of evidence indicate that N17 phosphorylation or pseudophosphorylation at any of the residues T3, S13 or S16, alone or in combination, modulates mHTT aggregation, subcellular localization and toxicity. Consequently, increasing N17 phosphorylation has been proposed as a potential therapeutic approach. However, developing genetic/pharmacological tools to quantify these phosphorylation events is necessary in order to subsequently develop tool modulators, which is difficult given the transient and incompletely penetrant nature of such post-translational modifications. Here we describe the first ultrasensitive sandwich immunoassay that quantifies HTT phosphorylated at residue S13 and demonstrate its utility for specific analyte detection in preclinical models of HD.


Assuntos
Proteína Huntingtina/análise , Animais , Células Cultivadas , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Camundongos , Mutação , Neurônios/química , Neurônios/metabolismo , Fosforilação , Agregados Proteicos , Processamento de Proteína Pós-Traducional
4.
Sci Rep ; 8(1): 7570, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29765112

RESUMO

Small molecules and antibodies each have advantages and limitations as therapeutics. Here, we present for the first time to our knowledge, the structure-guided design of "chemibodies" as small molecule-antibody hybrids that offer dual recognition of a single target by both a small molecule and an antibody, using DPP-IV enzyme as a proof of concept study. Biochemical characterization demonstrates that the chemibodies present superior DPP-IV inhibition compared to either small molecule or antibody component alone. We validated our design by successfully solving a co-crystal structure of a chemibody in complex with DPP-IV, confirming specific binding of the small molecule portion at the interior catalytic site and the Fab portion at the protein surface. The discovery of chemibodies presents considerable potential for novel therapeutics that harness the power of both small molecule and antibody modalities to achieve superior specificity, potency, and pharmacokinetic properties.


Assuntos
Dipeptidil Peptidase 4/química , Inibidores Enzimáticos/síntese química , Imunoconjugados/farmacologia , Animais , Anticorpos Monoclonais/química , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imunoconjugados/química , Modelos Moleculares , Ratos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
5.
ACS Comb Sci ; 15(9): 503-11, 2013 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-23927004

RESUMO

A platform that incorporates computational library design, parallel solution-phase synthesis, continuous flow hydrogenation, and automated high throughput purification and reformatting technologies was applied to the production of a 120-member library of 1-aryl-4-aminopiperidine analogues for drug discovery screening. The application described herein demonstrates the advantages of computational library design coupled with a flexible, modular approach to library synthesis. The enabling technologies described can be readily adopted by the traditional medicinal chemist without extensive training and lengthy process development times.


Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Triagem em Larga Escala , Simulação de Dinâmica Molecular , Piperidinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Algoritmos , Animais , Linhagem Celular , Permeabilidade da Membrana Celular/fisiologia , Humanos , Microssomos/química , Microssomos/metabolismo , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Ratos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Solubilidade , Suínos
6.
Bioorg Med Chem Lett ; 23(7): 2056-60, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23481650

RESUMO

Cdc7 kinase is responsible for the initiation and regulation of DNA replication and has been proposed as a target for cancer therapy. We have identified a class of Cdc7 inhibitors based on a substituted indole core. Synthesis of focused indole and azaindole analogs yielded potent and selective 5-azaindole Cdc7 inhibitors with improved intrinsic metabolic stability (ie 36). In parallel, quantum mechanical conformational analysis helped to rationalize SAR observations, led to a proposal of the preferred binding conformation in the absence of co-crystallography data, and allowed the design of 7-azaindole 37 as a second lead in this series.


Assuntos
Compostos Aza/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Compostos Aza/síntese química , Compostos Aza/química , Proteínas de Ciclo Celular/metabolismo , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 22(17): 5392-5, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22877629

RESUMO

Screening of the Amgen compound library led to the identification of 2-phenylamino-6-cyano-1H-benzimidazole 1a as a potent CK1 gamma inhibitor with excellent kinase selectivity and unprecedented CK1 isoform selectivity. Further structure-based optimization of this series resulted in the discovery of 1h which possessed good enzymatic and cellular potency, excellent CK1 isoform and kinase selectivity, and acceptable pharmacokinetic properties.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Caseína Quinase I/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Benzimidazóis/farmacocinética , Sítios de Ligação , Caseína Quinase I/química , Caseína Quinase I/metabolismo , Humanos , Camundongos , Modelos Moleculares , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Relação Estrutura-Atividade , beta Catenina/metabolismo
8.
J Med Chem ; 55(4): 1698-705, 2012 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-22263917

RESUMO

Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC(50) = 0.174 µM) during high throughput screening, with selectivity over the related kinase insulin-like growth factor-1 (IGF1R). The X-ray cocrystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.


Assuntos
Amidas/síntese química , Antineoplásicos/síntese química , Piperidinas/síntese química , Pirimidinas/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Quinase do Linfoma Anaplásico , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Transferência Ressonante de Energia de Fluorescência , Ensaios de Triagem em Larga Escala , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Conformação Proteica , Pirimidinas/química , Pirimidinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade
9.
Beilstein J Org Chem ; 7: 1141-9, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21915219

RESUMO

The performance of the ThalesNano H-Cube(®), a commercial packed bed flow hydrogenator, was evaluated in the context of small scale reaction screening and optimization. A model reaction, the reduction of styrene to ethylbenzene through a 10% Pd/C catalyst bed, was used to examine performance at various pressure settings, over sequential runs, and with commercial catalyst cartridges. In addition, the consistency of the hydrogen flow was indirectly measured by in-line UV spectroscopy. Finally, system contamination due to catalyst leaching, and the resolution of this issue, is described. The impact of these factors on the run-to-run reproducibility of the H-Cube(®) reactor for screening and reaction optimization is discussed.

10.
J Med Chem ; 53(17): 6398-411, 2010 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-20712346

RESUMO

The p38 mitogen-activated protein kinase (MAPK) plays an important role in the production of proinflammatory cytokines, making it an attractive target for the treatment of various inflammatory diseases. A series of pyridazinopyridinone compounds were designed as novel p38 kinase inhibitors. A structure-activity investigation identified several compounds possessing excellent potency in both enzyme and human whole blood assays. Among them, compound 31 exhibited good pharmacokinetic properties and showed excellent selectivity against other related kinases. In addition, 31 demonstrated efficacy in a collagen-induced arthritis disease model in rats.


Assuntos
Antirreumáticos/síntese química , Piridazinas/síntese química , Piridonas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Fator 2 Ativador da Transcrição/metabolismo , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Sítios de Ligação , Colágeno , Feminino , Humanos , Interleucina-8/biossíntese , Interleucina-8/sangue , Lipopolissacarídeos/farmacologia , Masculino , Modelos Moleculares , Fosforilação , Piridazinas/farmacocinética , Piridazinas/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/farmacologia
11.
Bioorg Med Chem Lett ; 20(12): 3573-8, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20493696

RESUMO

The membrane bound large-conductance, calcium-activated potassium channel (BKCa) is an important regulator of neuronal activity. Here we describe the identification and structure-activity relationship of a novel class of potent tetrahydroquinoline BKCa agonists. An example from this class of BKCa agonists was shown to depress the spontaneous neuronal discharges in an electrophysiological model of migraine.


Assuntos
Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/agonistas , Neurônios/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/patologia , Modelos Biológicos , Ratos , Relação Estrutura-Atividade , Núcleos do Trigêmeo/citologia
12.
J Med Chem ; 52(20): 6189-92, 2009 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-19764794

RESUMO

The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.


Assuntos
Isoquinolinas/farmacologia , Isoquinolinas/farmacocinética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Mutantes/antagonistas & inibidores , Mutação , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/síntese química , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Ratos , Especificidade por Substrato
13.
J Med Chem ; 51(9): 2744-57, 2008 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-18386885

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) channel antagonists may have clinical utility for the treatment of chronic nociceptive and neuropathic pain. We recently advanced a TRPV1 antagonist, 3 (AMG 517), into clinical trials as a new therapy for the treatment of pain. However, in addition to the desired analgesic effects, this TRPV1 antagonist significantly increased body core temperature following oral administration in rodents. Here, we report one of our approaches to eliminate or minimize the on-target hyperthermic effect observed with this and other TRPV1 antagonists. Through modifications of our clinical candidate, 3 a series of potent and peripherally restricted TRPV1 antagonists have been prepared. These analogues demonstrated on-target coverage in vivo but caused increases in body core temperature, suggesting that peripheral restriction was not sufficient to separate antagonism mediated antihyperalgesia from hyperthermia. Furthermore, these studies demonstrate that the site of action for TRPV1 blockade elicited hyperthermia is outside the blood-brain barrier.


Assuntos
Analgésicos/síntese química , Benzotiazóis/síntese química , Quinoxalinas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/farmacologia , Analgésicos/toxicidade , Animais , Benzotiazóis/farmacologia , Benzotiazóis/toxicidade , Barreira Hematoencefálica/metabolismo , Temperatura Corporal/efeitos dos fármacos , Capsaicina , Febre/induzido quimicamente , Masculino , Medição da Dor , Quinoxalinas/farmacologia , Quinoxalinas/toxicidade , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Telemetria
15.
J Med Chem ; 50(15): 3497-514, 2007 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-17585749

RESUMO

The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats.


Assuntos
Aminoquinolinas/síntese química , Analgésicos/síntese química , Pirimidinas/síntese química , Quinolinas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Temperatura Corporal/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Humanos , Hiperalgesia/prevenção & controle , Injeções Intravenosas , Masculino , Modelos Moleculares , Conformação Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Termodinâmica
16.
J Med Chem ; 50(15): 3515-27, 2007 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-17585750

RESUMO

A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade of capsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of the structure-activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elements required for activity in this series and resulted in the identification of subnanomolar TRPV1 antagonists. The most potent of these antagonists were thoroughly profiled in pharmacokinetic assays. Optimization of the heterocyclic A-region led to the design and synthesis of 23, a compound that potently blocked multiple modes of TRPV1 activation. Compound 23 was shown to be effective in a rodent "on-target" biochemical challenge model (capsaicin-induced flinch, ED50 = 0.33 mg/kg p.o.) and was antihyperalgesic in a model of inflammatory pain (CFA-induced thermal hyperalgesia, MED = 0.83 mg/kg, p.o.). Based on its in vivo efficacy and pharmacokinetic profile, compound 23 (N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide; AMG 517) was selected for further evaluation in human clinical trials.


Assuntos
Analgésicos/síntese química , Benzotiazóis/síntese química , Pirimidinas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzotiazóis/farmacocinética , Benzotiazóis/farmacologia , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Cães , Estabilidade de Medicamentos , Haplorrinos , Humanos , Hiperalgesia/tratamento farmacológico , Técnicas In Vitro , Inflamação/tratamento farmacológico , Masculino , Microssomos Hepáticos/metabolismo , Medição da Dor , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade , Canais de Cátion TRPV/genética
17.
J Med Chem ; 50(15): 3528-39, 2007 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-17585751

RESUMO

Based on the previously reported clinical candidate, AMG 517 (compound 1), a series of related piperazinylpyrimidine analogues were synthesized and evaluated as antagonists of the vanilloid 1 receptor (VR1 or TRPV1). Optimization of in vitro potency and physicochemical and pharmacokinetic properties led to the discovery of (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (16p), a potent TRPV1 antagonist [rTRPV1(CAP) IC50 = 3.7 nM] with excellent aqueous solubility (>or=200 microg/mL in 0.01 N HCl) and a reduced half-life (rat t1/2 = 3.8 h, dog t1/2 = 2.7 h, monkey t1/2 = 3.2 h) as compared to AMG 517. In addition, compound 16p was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo (ED50 = 1.9 mg/kg, p.o. in the capsaicin-induced flinch model in rats) and was also effective at reducing thermal hyperalgesia induced by complete Freund's adjuvant in rats (MED = 1 mg/kg, p.o). Based on its improved overall profile, compound 16p (AMG 628) was selected as a second-generation candidate for further evaluation in human clinical trials as a potential new treatment for chronic pain.


Assuntos
Analgésicos/síntese química , Benzotiazóis/síntese química , Pirimidinas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzotiazóis/química , Benzotiazóis/farmacocinética , Benzotiazóis/farmacologia , Células CHO , Cricetinae , Cricetulus , Cães , Estabilidade de Medicamentos , Haplorrinos , Humanos , Hiperalgesia/tratamento farmacológico , Masculino , Medição da Dor , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Canais de Cátion TRPV/genética , Termodinâmica
18.
Bioorg Med Chem Lett ; 15(23): 5211-7, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16203144

RESUMO

A thiazole derivative, 2-(2,6-dichlorobenzyl)-N-(4-isopropylphenyl) thiazole-4-carboxamide (1), was identified as a TRPV1 antagonist. We synthesized various thiazole analogs and evaluated them for their ability to block capsaicin- or acid-induced calcium influx in TRPV1-expressing CHO cells. The IC(50) values of the most potent antagonists were ca. 0.050microM in these assays.


Assuntos
Amidas/química , Amidas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Amidas/síntese química , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Estrutura Molecular , Ácido Oxâmico/síntese química , Ácido Oxâmico/química , Ácido Oxâmico/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química
19.
J Med Chem ; 48(1): 71-90, 2005 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-15634002

RESUMO

The vanilloid receptor-1 (TRPV1 or VR1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role in regulating the function of sensory nerves. A growing body of evidence demonstrates the therapeutic potential of TRPV1 modulators, particularly in the management of pain. As a result of our screening efforts, we identified (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (1), an antagonist that blocks the capsaicin-induced and pH-induced uptake of (45)Ca(2+) in TRPV1-expressing Chinese hamster ovary cells with IC(50) values of 17 +/- 5 and 150 +/- 80 nM, respectively. In this report, we describe the synthesis and structure-activity relationship of a series of N-aryl cinnamides, the most potent of which (49a and 49b) exhibit good oral bioavailability in rats (F(oral) = 39% and 17%, respectively).


Assuntos
Cinamatos/química , Cinamatos/farmacologia , Canais Iônicos/antagonistas & inibidores , Administração Oral , Animais , Bioquímica/métodos , Disponibilidade Biológica , Células CHO/efeitos dos fármacos , Células CHO/metabolismo , Cálcio/metabolismo , Capsaicina/farmacologia , Cinamatos/farmacocinética , Cricetinae , Cricetulus , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Canais Iônicos/genética , Masculino , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Canais de Cátion TRPV
20.
J Pharmacol Exp Ther ; 313(1): 474-84, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15615864

RESUMO

The vanilloid receptor 1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel expressed by peripheral sensory neurons. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Here, we describe the in vitro and in vivo pharmacology of a novel TRPV1 antagonist, AMG 9810, (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide. AMG 9810 is a competitive antagonist of capsaicin activation (IC50 value for human TRPV1, 24.5 +/- 15.7 nM; rat TRPV1, 85.6 +/- 39.4 nM) and blocks all known modes of TRPV1 activation, including protons (IC50 value for rat TRPV1, 294 +/- 192 nM; human TRPV1, 92.7 +/- 72.8 nM), heat (IC50 value for rat TRPV1, 21 +/- 17 nM; human TRPV1, 15.8 +/- 10.8 nM), and endogenous ligands, such as anandamide, N-arachidonyl dopamine, and oleoyldopamine. AMG 9810 blocks capsaicin-evoked depolarization and calcitonin gene-related peptide release in cultures of rat dorsal root ganglion primary neurons. Screening of AMG 9810 against a panel of G protein-coupled receptors and ion channels indicated selectivity toward TRPV1. In vivo, AMG 9810 is effective at preventing capsaicin-induced eye wiping in a dose-dependent manner, and it reverses thermal and mechanical hyperalgesia in a model of inflammatory pain induced by intraplantar injection of complete Freund's adjuvant. At effective doses, AMG 9810 did not show any significant effects on motor function, as measured by open field locomotor activity and motor coordination tests. AMG 9810 is the first cinnamide TRPV1 antagonist reported to block capsaicin-induced eye wiping behavior and reverse hyperalgesia in an animal model of inflammatory pain.


Assuntos
Acrilamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Hiperalgesia/tratamento farmacológico , Receptores de Droga/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Células CHO , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/antagonistas & inibidores , Células Cultivadas , Cricetinae , Adjuvante de Freund , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Temperatura Alta , Humanos , Hiperalgesia/induzido quimicamente , Inflamação/complicações , Inflamação/patologia , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Medição da Dor/efeitos dos fármacos , Técnicas de Patch-Clamp , Prótons , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transfecção
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