RESUMO
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 µM.
Assuntos
Analgésicos/farmacologia , Gânglios Espinais/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/tratamento farmacológico , Bloqueadores dos Canais de Sódio/farmacologia , Nervos Espinhais/efeitos dos fármacos , Compostos de Espiro/farmacologia , Analgésicos/química , Animais , Estrutura Molecular , Técnicas de Patch-Clamp , Quinoxalinas/química , Ratos , Bloqueadores dos Canais de Sódio/química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.
Assuntos
Descoberta de Drogas , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Quinoxalinas/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Compostos de Espiro/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Quinoxalinas/síntese química , Quinoxalinas/química , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
The identification of potent and orally active dihydroimidazoisoquinolines as PDE 10A inhibitors is reported. The SAR development led to the discovery of compound 35 as a potent, selective, and orally active PDE10A inhibitor. Compound 35 inhibited MK-801-induced hyperactivity at 3mg/kg and displayed a 10-fold separation between the minimal effective doses for inhibition of MK-801-induced hyperactivity and hypolocomotion in rats.
Assuntos
Hipercinese/tratamento farmacológico , Imidazóis/síntese química , Isoquinolinas/síntese química , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/química , Psicotrópicos/síntese química , Animais , Área Sob a Curva , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Maleato de Dizocilpina , Haplorrinos , Humanos , Hipercinese/induzido quimicamente , Hipercinese/enzimologia , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacocinética , Masculino , Modelos Moleculares , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/farmacocinética , Diester Fosfórico Hidrolases/metabolismo , Psicotrópicos/administração & dosagem , Psicotrópicos/farmacocinética , Ratos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/enzimologia , Relação Estrutura-AtividadeRESUMO
High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a â¼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.
Assuntos
Inibidores Enzimáticos/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Pirazolonas/farmacologia , Quinolinas/farmacologia , Esquizofrenia/tratamento farmacológico , Administração Oral , Animais , Cristalografia por Raios X , Maleato de Dizocilpina/antagonistas & inibidores , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Ensaios de Triagem em Larga Escala , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazolonas/administração & dosagem , Pirazolonas/química , Quinolinas/administração & dosagem , Quinolinas/química , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3-10 mg/kg) and fear-potentiated startle (3-10 mg/kg) tests, a guinea pig pup vocalization test (1-3 mg/kg), as well as in mouse Geller-Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70-100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species.
Assuntos
Ansiolíticos/efeitos adversos , Ansiolíticos/farmacologia , Compostos Azabicíclicos/efeitos adversos , Compostos Azabicíclicos/farmacologia , Receptores Opioides/agonistas , Animais , Ansiolíticos/sangue , Ansiolíticos/farmacocinética , Compostos Azabicíclicos/sangue , Compostos Azabicíclicos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Temperatura Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Relação Dose-Resposta a Droga , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Técnicas de Inativação de Genes , Cobaias , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Ratos , Receptores Opioides/deficiência , Receptores Opioides/genética , Teste de Desempenho do Rota-Rod , Especificidade da Espécie , Vocalização Animal/efeitos dos fármacos , Receptor de NociceptinaRESUMO
The study of human metabolism of endo-8[bis(2-chlorophenyl)methyl]-3-(2-pyrimidinyl)-8-azabicyclo[3.2.1]octan-3-ol (SCH 486757) after a 200-mg oral dose of the drug to healthy volunteers in the first-in-human study is presented. The structural elucidation of two unique metabolites, which were detected in the process of metabolite characterization in human plasma and urine by liquid chromatography-mass spectrometry (LC-MS), is described. These metabolites (M27 and M34) were initially detected in human plasma at high levels (>35% of the LC-MS response of the parent drug). Additional LC-MS experiments (hydrogen/deuterium exchange and accurate mass measurement) were used to determine structures of metabolites. It was found that both metabolites were formed through a loss of the C-C bridge from the tropane moiety with the conversion into a substituted pyridinium compound. This metabolic process has not been reported previously. Because of the apparent high abundance of metabolites based on the LC-MS response, actual circulating amounts of these metabolites relative to the parent drug were determined semiquantitatively to evaluate their coverage in preclinical species. With the use of reference standards, it was shown that the LC-MS response of M27 and M34 in human plasma was much higher than that of the parent compound. Actual amounts of M27 and M34 metabolites were less than 5% of the level of the parent drug; therefore, additional assessment was not required.
Assuntos
Antitussígenos/metabolismo , Compostos Azabicíclicos/metabolismo , Compostos de Piridínio/metabolismo , Pirimidinas/metabolismo , Receptores Opioides/agonistas , Animais , Antitussígenos/sangue , Antitussígenos/farmacocinética , Antitussígenos/farmacologia , Antitussígenos/urina , Compostos Azabicíclicos/sangue , Compostos Azabicíclicos/farmacocinética , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/urina , Biotransformação , Cromatografia Líquida de Alta Pressão , Humanos , Masculino , Conformação Molecular , Compostos de Piridínio/sangue , Compostos de Piridínio/química , Compostos de Piridínio/urina , Pirimidinas/sangue , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/urina , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Receptor de NociceptinaRESUMO
The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid mu receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure-activity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed.
Assuntos
Ansiolíticos/síntese química , Antitussígenos/síntese química , Ansiedade/tratamento farmacológico , Tosse/tratamento farmacológico , Ligantes , Tropanos/síntese química , Animais , Ansiolíticos/farmacologia , Antitussígenos/farmacologia , Capsaicina/química , Química Farmacêutica/métodos , Desenho de Fármacos , Cobaias , Humanos , Receptor de Pregnano X , Receptores Opioides/química , Receptores de Esteroides/química , Relação Estrutura-Atividade , Tropanos/farmacologia , Receptor de NociceptinaRESUMO
A series of 4-[2-(aminomethyl)phenyl]-1-[bis(2-chlorophenyl)methyl]-4-hydroxypiperidine analogs has been identified as nociceptin receptor ligands. These compounds display high affinity and functional activity at the nociceptin receptor. The synthesis and structure-activity relationships at the C-4 phenyl and N-1 positions are described and the antitussive activity of a selected compound is reported.
Assuntos
Antitussígenos/química , Antitussígenos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores Opioides/agonistas , Animais , Antitussígenos/síntese química , Células CHO , Cricetinae , Cricetulus , Cobaias , Humanos , Ligantes , Piperidinas/síntese química , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
A series of 4-hydroxy-4-phenylpiperidines have been synthesized and bind to the nociceptin receptor with high affinity. The synthesis and structure-activity relationships at the N-1 and C-4 are described.