RESUMEN
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.
Asunto(s)
Analgésicos/farmacología , Ganglios Espinales/efectos de los fármacos , Canal de Sodio Activado por Voltaje NAV1.7/química , Neuralgia/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/farmacología , Nervios Espinales/efectos de los fármacos , Compuestos de Espiro/farmacología , Analgésicos/química , Animales , Estructura Molecular , Técnicas de Placa-Clamp , Quinoxalinas/química , Ratas , Bloqueadores de los Canales de Sodio/química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Descubrimiento de Drogas , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Quinoxalinas/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Compuestos de Espiro/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Quinoxalinas/síntesis química , Quinoxalinas/química , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Hipercinesia/tratamiento farmacológico , Imidazoles/síntesis química , Isoquinolinas/síntesis química , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/química , Psicotrópicos/síntesis química , Animales , Área Bajo la Curva , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Maleato de Dizocilpina , Haplorrinos , Humanos , Hipercinesia/inducido químicamente , Hipercinesia/enzimología , Imidazoles/administración & dosificación , Imidazoles/farmacocinética , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacocinética , Masculino , Modelos Moleculares , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/farmacocinética , Hidrolasas Diéster Fosfóricas/metabolismo , Psicotrópicos/administración & dosificación , Psicotrópicos/farmacocinética , Ratas , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/enzimología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazolonas/farmacología , Quinolinas/farmacología , Esquizofrenia/tratamiento farmacológico , Administración Oral , Animales , Cristalografía por Rayos X , Maleato de Dizocilpina/antagonistas & inhibidores , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Ensayos Analíticos de Alto Rendimiento , Humanos , Modelos Moleculares , Estructura Molecular , Pirazolonas/administración & dosificación , Pirazolonas/química , Quinolinas/administración & dosificación , Quinolinas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of pyrazoloquinolines, possessing (hetero)arylhydroxymethyl substituents at the quinoline C-4 position were evaluated as PDE10A inhibitors. Among these, methylpyrimidyl analogue 15 was identified as having good rodent and monkey exposure, and a MED of 10 mg/kg in an in vivo model.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Quinolinas/química , Quinolinas/farmacología , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Haplorrinos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Concentración 50 Inhibidora , Estructura Molecular , Pirazolonas/síntesis química , Pirazolonas/química , Pirazolonas/farmacocinética , Pirazolonas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacocinética , RatasRESUMEN
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.
Asunto(s)
Ansiolíticos/efectos adversos , Ansiolíticos/farmacología , Compuestos de Azabiciclo/efectos adversos , Compuestos de Azabiciclo/farmacología , Receptores Opioides/agonistas , Animales , Ansiolíticos/sangre , Ansiolíticos/farmacocinética , Compuestos de Azabiciclo/sangre , Compuestos de Azabiciclo/farmacocinética , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Temperatura Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Relación Dosis-Respuesta a Droga , Miedo/efectos de los fármacos , Miedo/fisiología , Femenino , Técnicas de Inactivación de Genes , Cobayas , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Ratas , Receptores Opioides/deficiencia , Receptores Opioides/genética , Prueba de Desempeño de Rotación con Aceleración Constante , Especificidad de la Especie , Vocalización Animal/efectos de los fármacos , Receptor de NociceptinaRESUMEN
We describe the pharmacological and pharmacokinetic profiles of SCH 486757, a nociceptin/orphanin FQ peptide (NOP) receptor agonist that has recently entered human clinical trials for cough. SCH 486757 selectively binds human NOP receptor (K(i)=4.6+/-0.61nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01-1mg/kg) suppressed cough at 2, 4, and 6h post oral administration with a maximum efficacy occurring at 4h equivalent to codeine, hydrocodone, dextromethorphan and baclofen. The antitussive effects of SCH 486757 (3.0mg/kg, p.o.) was blocked by the NOP receptor antagonist J113397 (12mg/kg, i.p.) but not by naltrexone (10mg/kg, p.o.). SCH 486757 does not produce tolerance to its antitussive activity after a 5-day BID dosing regimen. After acute and chronic dosing paradigms, SCH 486757 (1mg/kg) inhibited capsaicin-evoked coughing by 46+/-9% and 40+/-11%, respectively. In a feline mechanically-evoked cough model, SCH 486757 produces a maximum inhibition of cough and expiratory abdominal electromyogram amplitude of 59 and 61%, respectively. SCH 486757 did not significantly affect inspiratory electromyogram amplitude. We examined the abuse potential of SCH 486757 (10mg/kg, p.o.) in a rat conditioned place preference procedure which is sensitive to classical drugs of abuse, such as amphetamine and morphine. SCH 486757 was without effect in this model. Finally, SCH 486757 displays a good oral pharmacokinetic profile in the guinea pig, rat and dog. We conclude that SCH 486757 has a favorable antitussive profile in preclinical animal models.
Asunto(s)
Antitusígenos/uso terapéutico , Tos/tratamiento farmacológico , Receptores Opioides/agonistas , Animales , Compuestos de Azabiciclo/farmacología , Gatos , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Cobayas , Masculino , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Opioides/metabolismo , Receptor de NociceptinaRESUMEN
BACKGROUND: Previous studies have demonstrated that nociceptin/orphanin FQ (N/OFQ), the endogenous peptide ligand for the G-protein-coupled NOP receptor, inhibits cough in experimental models. SCH 225288 is a nonpeptide, orally active NOP agonist that may provide the foundation for the development of novel treatments for cough. METHODS: First we characterized the selectivity of SCH 225288 in human receptor binding assays. Afterwards, the antitussive activity of SCH 225288 was studied in three mechanistically distinct cough models. Specifically, we observed the cough-suppressant effect of SCH 225288 in a guinea pig capsaicin irritant-evoked cough model, a feline mechanically induced cough model and finally in a canine Bordetella bronchiseptica disease model. RESULTS: SCH 225288 selectively binds human NOP receptor (K(i) = 0.38 +/- 0.02 nmol/l) over classical opioid receptors (COR). In a guinea pig capsaicin cough model, SCH 225288 (0.1-1 mg/kg) suppressed cough at 2, 4, and 6 h after oral administration. The antitussive effect of SCH 225288 (3.0 mg/kg, p.o.) was blocked by the NOP antagonist J113397 (12 mg/kg, i.p.) but not by the classical opioid receptor (COR) antagonist, naltrexone (3.0 mg/kg, i.p.). In the anesthetized cat, we evaluated the effects of SCH 225288 given either intravenously or via the intravertebral artery against the increases in cough number and respiratory expiratory and inspiratory muscle (rectus abdominis and parasternal) electromyographic (EMG) activities due to perturbations of the intrathoracic trachea. SCH 225288 (0.03-3.0 mg/kg, i.v.) inhibited both cough number and abdominal EMG amplitudes. Similarly, SCH 225288 (0.001-0.3 mg/kg) administered intra-arterially also diminished cough number and abdominal EMG amplitudes. No significant effect of the drug was noted on parasternal EMG activity. Finally, we studied the antitussive actions of SCH 225288 (1.0 mg/kg) in a canine B. bronchiseptica disease model. In this model, dogs were challenged intranasally with B. bronchiseptica. Comparisons were made between a vehicle group, an SCH 225288 (1.0 mg/kg, p.o., q.d.) and a butorphanol (0.6 mg/kg, p.o., b.i.d.) group on the mean change in cough scores from baseline values and days 6-9 after B. bronchiseptica challenge. SCH 225288 (1.0 mg/kg, p.o., q.d.) displayed a positive antitussive tendency (p = 0.06) to inhibit B. bronchiseptica cough whereas butorphanol (0.6 mg/kg, p.o., b.i.d.) was devoid of antitussive activity. CONCLUSIONS: Taken together, the present data show that SCH 225288 is a potent and effective antitussive agent in animal models of cough. Furthermore, these findings indicate that NOP agonists represent a promising new therapeutic approach for the treatment of cough without the side effect liabilities associated with opioid antitussives.
Asunto(s)
Antitusígenos/farmacología , Tos/tratamiento farmacológico , Receptores Opioides/agonistas , Tropanos/farmacología , Animales , Antitusígenos/administración & dosificación , Antitusígenos/efectos adversos , Infecciones por Bordetella/tratamiento farmacológico , Infecciones por Bordetella/veterinaria , Bordetella bronchiseptica/aislamiento & purificación , Células CHO , Capsaicina , Gatos , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Femenino , Cobayas , Humanos , Masculino , Especificidad de la Especie , Factores de Tiempo , Tropanos/administración & dosificación , Tropanos/efectos adversos , Receptor de NociceptinaRESUMEN
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.
Asunto(s)
Ansiolíticos/síntesis química , Antitusígenos/síntesis química , Ansiedad/tratamiento farmacológico , Tos/tratamiento farmacológico , Ligandos , Tropanos/síntesis química , Animales , Ansiolíticos/farmacología , Antitusígenos/farmacología , Capsaicina/química , Química Farmacéutica/métodos , Diseño de Fármacos , Cobayas , Humanos , Receptor X de Pregnano , Receptores Opioides/química , Receptores de Esteroides/química , Relación Estructura-Actividad , Tropanos/farmacología , Receptor de NociceptinaRESUMEN
Orphanin FQ/nociceptin (OFQ/N) is the endogenously occurring peptide ligand for the nociceptin opioid receptor (NOP) that produces anxiolytic-like effects in mice and rats. The present study assessed the anxiolytic-like activity of 8-[bis(2-methylphenyl)-methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510), a novel potent piperidine NOP agonist (EC(50) = 12 nM) that binds with high affinity (K(i) = 0.3 nM) and functional selectivity (>50-fold over the mu-, kappa-, and delta-opioid receptors). The anxiolytic-like activity and side-effect profile of SCH 221510 were assessed in a variety of models and the benzodiazepine, chlordiazepoxide (CDP), was included for comparison. The effects of chronic dosing of SCH 221510 were also assessed. Furthermore, the specificity of the anxiolytic-like effect of SCH 221510 was investigated with the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and the opioid receptor antagonist naltrexone. Like CDP (1-30 mg/kg i.p.), SCH 221510 (1-30 mg/kg p.o.) produced anxiolytic-like effects in the elevated plus-maze (rat and gerbil), Vogel conflict (rat), conditioned lick suppression (rat), fear-potentiated startle (rat), and pup separation-induced vocalization (guinea pig) assays. In the Vogel conflict, the anxiolytic-like effect of SCH 221510 (10 mg/kg) was attenuated by J-113397 (3-10 mg/kg p.o.), but not naltrexone (3-30 mg/kg i.p.). Additionally, the anxiolytic-like effects of SCH 221510 did not change appreciably following 14-day b.i.d. dosing in rats (10 mg/kg). Furthermore, unlike CDP, SCH 221510 (3-30 mg/kg) produced anxiolytic-like activity at doses that did not disrupt overt behavior. Collectively, these data suggest that NOP agonists such as SCH 221510 may have an anxiolytic-like profile similar to benzodiazepines, with a reduced side-effect liability.
Asunto(s)
Ansiolíticos/farmacología , Compuestos de Azabiciclo/farmacología , Conducta Animal/efectos de los fármacos , Receptores Opioides/agonistas , Animales , Animales Recién Nacidos , Ansiolíticos/química , Compuestos de Azabiciclo/química , Bencimidazoles/farmacología , Células CHO , Cricetinae , Cricetulus , Femenino , Gerbillinae , Cobayas , Humanos , Masculino , Estructura Molecular , Antagonistas de Narcóticos , Piperidinas/farmacología , Unión Proteica , Ratas , Ratas Wistar , Receptores Opioides/metabolismo , Receptor de NociceptinaRESUMEN
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.
Asunto(s)
Antitusígenos/química , Antitusígenos/farmacología , Piperidinas/química , Piperidinas/farmacología , Receptores Opioides/agonistas , Animales , Antitusígenos/síntesis química , Células CHO , Cricetinae , Cricetulus , Cobayas , Humanos , Ligandos , Piperidinas/síntesis química , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
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.