RESUMO
Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.
Assuntos
Descoberta de Drogas , Antagonistas dos Receptores de Orexina , Piridinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Tiazóis/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
We have identified and synthesized a series of diaryl substituted pyrazoles as potent antagonists of the chemokine receptor subtype 2. Structure-activity relationship studies directed toward improving the potency led to the discovery of 23 (IC50 = 6 nM).
Assuntos
Pirazóis/síntese química , Pirazóis/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Quimiotaxia/efeitos dos fármacos , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Monócitos/efeitos dos fármacos , Oxirredução , Receptores CCR2 , Receptores de Quimiocinas/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
We have identified and synthesized a brain penetrant propanoic acid as an allosteric potentiator of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency, level of potentiation and brain penetration led to the discovery of 8 (EC50=1200 nM, 77% potentiation, 119% brain/plasma in rat, 20 mpk i.p., brain level of 5700 nM).
Assuntos
Encéfalo/fisiologia , Butanos/síntese química , Butanos/farmacologia , Propionatos/síntese química , Propionatos/farmacologia , Receptores de Glutamato Metabotrópico/fisiologia , Regulação Alostérica , Animais , Encéfalo/efeitos dos fármacos , Butanos/farmacocinética , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cinética , Conformação Molecular , Éteres Fenílicos , Propionatos/farmacocinética , Ratos , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
We have identified and synthesized a series of phenyl-tetrazolyl and 4-thiopyridyl indanones as allosteric potentiators of the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of potentiation, as well as PK properties, led to the discovery of 28 (EC50=186 nM), which displayed activity in a rodent model for schizophrenia.
Assuntos
Indanos/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Regulação Alostérica , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Indanos/farmacocinética , Modelos Químicos , Estrutura Molecular , Ligação Proteica , Ratos , Esquizofrenia/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
We have identified and synthesized a series of aryl-tetrazoyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of potentiation led to the discovery of 22 (EC(50)=93nM, 128% potentiation).
Assuntos
Acetofenonas/síntese química , Receptores de Glutamato Metabotrópico/agonistas , Tetrazóis/síntese química , Acetofenonas/química , Acetofenonas/farmacologia , Regulação Alostérica , Estereoisomerismo , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologiaRESUMO
We have identified and synthesized a series of 4-thiopyridyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward replacement of the tetrazole in the initial lead led to the discovery of 16 (EC(50)=340 nM), which showed improved brain penetration over the initial lead.