RESUMO
A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.
Assuntos
Depressão/tratamento farmacológico , Desenho de Fármacos , Antagonistas dos Receptores de Neurocinina-1 , Piridinas/síntese química , Antagonistas da Serotonina , Animais , Modelos Animais de Doenças , Gerbillinae , Concentração Inibidora 50 , Estrutura Molecular , Piridinas/química , Piridinas/uso terapêutico , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/uso terapêuticoRESUMO
Several studies have suggested that neurokinin-1 (NK1) receptor antagonists may have therapeutic potential as novel antidepressant drugs. To test these compounds preclinically, gerbils have become one of the preferred species in that they demonstrate close NK1 receptor homology with humans and bind NK1 antagonists with higher affinity than rats and mice. The intent of the present study was to determine whether the forced-swim test (FST), one of the most commonly used animal tests of antidepressant-like activity, could be adapted for use with the gerbil. Critical factors in the establishment of this assay included swim tank diameter, weight, and sex of the animals tested. Pharmacological validation of the FST using standard antidepressant compounds (eg fluoxetine, paroxetine, desipramine) resulted in decreased immobility time during the test, indicative of an antidepressant-like effect. Similar to results reported for the rat and mouse FST, the antipsychotic drug haloperidol increased immobility, whereas the psychostimulant, amphetamine decreased immobility, and anxiolytic drugs (eg buspirone) had no effect. Investigation into the locomotor effects of all compounds tested was consistent with previous reports in other species, with the exception of paroxetine, which produced hyperactivity at therapeutically effective doses in gerbils. In addition to standard antidepressants, NK1 antagonists (L-733060, MK-869, and CP-122721) all reduced immobility in the gerbil FST without affecting locomotor activity. Overall, these results suggest that the gerbil is an ideal species for use in the FST, and that this paradigm may have predictive validity for identifying novel antidepressant compounds.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/psicologia , Antagonistas dos Receptores de Neurocinina-1 , Natação/psicologia , Inibidores da Captação Adrenérgica/uso terapêutico , Anfetamina/uso terapêutico , Animais , Antidepressivos de Segunda Geração/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Antipsicóticos/farmacologia , Peso Corporal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/uso terapêutico , Interpretação Estatística de Dados , Feminino , Gerbillinae , Masculino , Atividade Motora/efeitos dos fármacos , Reprodutibilidade dos Testes , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Caracteres SexuaisRESUMO
Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.
Assuntos
Antidepressivos/farmacologia , Indazóis/farmacologia , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Administração Oral , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/toxicidade , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Gerbillinae , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/toxicidade , Camundongos , Estrutura Molecular , Antagonistas dos Receptores de Neurocinina-1/síntese química , Antagonistas dos Receptores de Neurocinina-1/química , Antagonistas dos Receptores de Neurocinina-1/toxicidade , Ratos , Receptores da Neurocinina-1/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Relação Estrutura-Atividade , Regulador Transcricional ERG/metabolismoRESUMO
The formation of a reactive intermediate was found to be responsible for CYP3A4 metabolism-dependent inhibition (MDI) observed with (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenyl-acrylamide (1). Structure-3A4 MDI relationship studies culminated in the discovery of a difluoro analogue, (S)-N-[1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl]-3-(4-fluoro-phenyl)acrylamide (2), as an orally bioavailable KCNQ2 opener free of CYP3A4 MDI.
Assuntos
Cinamatos/síntese química , Inibidores das Enzimas do Citocromo P-450 , Flúor/química , Morfolinas/síntese química , Canais de Potássio/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular , Cinamatos/metabolismo , Cinamatos/farmacologia , Citocromo P-450 CYP3A , Modelos Animais de Doenças , Injeções Intravenosas , Ativação do Canal Iônico , Canal de Potássio KCNQ2 , Masculino , Potenciais da Membrana , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Morfolinas/metabolismo , Morfolinas/farmacologia , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/fisiopatologia , Técnicas de Patch-Clamp , Canais de Potássio/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide (2) was synthesized as an orally bioavailable KCNQ2 potassium channel opener. In a rat model of migraine, 2 demonstrated significant oral activity in reducing the total number of cortical spreading depressions induced by potassium chloride.
Assuntos
Acrilamidas/síntese química , Córtex Cerebral/efeitos dos fármacos , Transtornos de Enxaqueca/fisiopatologia , Morfolinas/síntese química , Canais de Potássio/efeitos dos fármacos , Acrilamidas/química , Acrilamidas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Cães , Humanos , Ativação do Canal Iônico , Canal de Potássio KCNQ2 , Transtornos de Enxaqueca/metabolismo , Morfolinas/química , Morfolinas/farmacologia , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Técnicas de Patch-Clamp , Canais de Potássio/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Xenopus laevisRESUMO
The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.