Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 59(10): 4753-68, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27067148

RESUMO

Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (-)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (-)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients.


Assuntos
Canais de Cálcio/metabolismo , Descoberta de Drogas , Receptores de AMPA/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores de AMPA/metabolismo
2.
Bioorg Med Chem Lett ; 24(24): 5572-5575, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25466177

RESUMO

Osteoarthritis (OA) and the associated joint pain are highly prevalent and a leading cause of disability. We have previously reported the identification of a series of purines as selective CB2 agonists and the identification of compound 1 as a clinical candidate for the treatment of joint pain. In this article we describe the further SAR development of the purine scaffold leading to the discovery of compound 6 as a potent, CNS penetrating CB2 agonist with high selectivity for CB2 over CB1 and oral efficacy in animal models of chronic OA pain.


Assuntos
Agonistas de Receptores de Canabinoides/uso terapêutico , Dor Crônica/tratamento farmacológico , Piperazinas/química , Purinas/química , Receptor CB2 de Canabinoide/agonistas , Animais , Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/farmacocinética , Modelos Animais de Doenças , Cães , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Osteoartrite/tratamento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade
3.
J Med Chem ; 56(14): 5722-33, 2013 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-23795771

RESUMO

A focused screening strategy identified thienopyrimidine 12 as a cannabinoid receptor type 2 agonist (hCB2) with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a new more polar series of purine CB2 agonists. Examples from this novel scaffold were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1, often having no CB1 agonist activity at the highest concentration measured (>100 µM). Compound 26 is a centrally penetrant molecule which possesses good biopharmaceutical properties, is highly water-soluble, and demonstrates robust oral activity in rodent models of joint pain. In addition, the peripherally restricted molecule 22 also demonstrated significant efficacy in the same analgesic model of rodent inflammatory pain.


Assuntos
Osteoartrite/tratamento farmacológico , Purinas/síntese química , Receptor CB2 de Canabinoide/agonistas , Animais , Cães , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Células HEK293 , Humanos , Masculino , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 23(5): 1249-52, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23374867

RESUMO

A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.


Assuntos
Amidas/química , Amidas/farmacologia , Ciclopropanos/química , Ciclopropanos/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica/efeitos dos fármacos , Amidas/farmacocinética , Animais , Comportamento Animal/efeitos dos fármacos , Ciclopropanos/farmacocinética , Ácido Glutâmico/química , Ácido Glutâmico/metabolismo , Indazóis/química , Indazóis/farmacocinética , Indazóis/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/química , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologia
5.
Bioorg Med Chem Lett ; 22(15): 4962-6, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22765893

RESUMO

A focused screening strategy identified thienopyrimidine 1 as a hCB2 cannabinoid receptor agonist with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a less lipophilic purine core. Examples from this novel series were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1. Compound 10 possesses good biopharmaceutical properties, is highly water soluble and demonstrates robust oral activity in rodent models of joint pain.


Assuntos
Furanos/química , Purinas/química , Receptor CB2 de Canabinoide/agonistas , Animais , Avaliação Pré-Clínica de Medicamentos , Furanos/farmacocinética , Furanos/uso terapêutico , Meia-Vida , Humanos , Dor/tratamento farmacológico , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 22(7): 2514-7, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22386665

RESUMO

The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.


Assuntos
Amidas/síntese química , Analgésicos/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Dor/tratamento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tiazóis/síntese química , Administração Oral , Amidas/administração & dosagem , Amidas/farmacocinética , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Humanos , Dor/metabolismo , Medição da Dor , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/administração & dosagem , Tiazóis/farmacocinética
7.
J Pharmacol Exp Ther ; 318(3): 1108-17, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16738207

RESUMO

Here we report the discovery, by high-throughput screening, of three novel (2-amino-5-keto)thiazole compounds that act as selective potentiators of nicotinic acetylcholine receptors. Compound selectivity was assessed at seven human nicotinic acetylcholine receptors (alpha1beta1gammadelta, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2, alpha4beta4, and alpha7) expressed in mammalian cells or Xenopus oocytes. At alpha2beta4, alpha4beta2, alpha4beta4, and alpha7, but not alpha1beta1gammadelta, alpha3beta2, or alpha3beta4, submaximal responses to nicotinic agonists were potentiated in a concentration-dependent manner by all compounds. At similar concentrations, no potentiation of 5-hydroxytryptamine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABA(A), and N-methyl-d-aspartate receptors or voltage-gated Na(+) and Ca(2+) channels was observed. Furthermore, these compounds did not inhibit acetylcholine esterase. Further profiling revealed that these compounds enhanced the potency and maximal efficacy of a range of nicotinic agonists at alpha4beta2 nicotinic acetylcholine receptors, a profile typical of allosteric potentiators. At concentrations required for potentiation, the compounds did not displace [(3)H]epibatidine from the agonist-binding site, and potentiation was observed at all agonist concentrations, suggesting a noncompetitive mechanism of action. Blockade of common second messenger systems did not affect potentiation. At concentrations higher then required for potentiation the compounds also displayed intrinsic agonist activity, which was blocked by competitive and noncompetitive nicotinic acetylcholine receptor (nAChR) antagonists. These novel selective nicotinic receptor potentiators should help in clarifying the potential therapeutic utility of selective nAChR modulation for the treatment of central nervous system disorders.


Assuntos
Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Sinergismo Farmacológico , Galantamina/farmacologia , Humanos , Subunidades Proteicas , Piridinas/farmacologia , Receptores Nicotínicos/química , Proteínas Recombinantes/efeitos dos fármacos , Xenopus laevis
8.
J Med Chem ; 45(12): 2624-43, 2002 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-12036372

RESUMO

A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure-activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA.


Assuntos
Azepinas/síntese química , Benzofenonas/síntese química , Inibidores Enzimáticos/síntese química , Hidroxibenzoatos/síntese química , Proteína Quinase C/antagonistas & inibidores , Azepinas/química , Benzofenonas/química , Inibidores Enzimáticos/química , Humanos , Hidroxibenzoatos/química , Isoenzimas/antagonistas & inibidores , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 12(6): 883-6, 2002 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-11958985

RESUMO

Tricyclic isoxazoles were identified from a screen as a novel class of selective multidrug resistance protein (MRP1) inhibitors. From a screen lead, SAR efforts resulted in the preparation of LY 402913 (9h), which inhibits MRP1 and reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC(50)=0.90 microM), while showing no inherent cytotoxicity. Additionally, LY 402913 inhibits ATP-dependent, MRP1-mediated LTC(4) uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC(50)=1.8 microM). LY 402913 also shows selectivity ( approximately 22-fold) against the related transporter, P-glycoprotein, in HL60/Adr and HL60/Vinc cells. Finally, when dosed in combination with the oncolytic MRP1 substrate vincristine, LY 402913 delays the growth of MRP1-overexpressing tumors in vivo.


Assuntos
Isoxazóis/síntese química , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistência a Medicamentos , Sinergismo Farmacológico , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Leucotrieno C4/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Vincristina/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...