RESUMO
As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT(6) antagonists. The synthesis and detailed SAR of this class of compounds are reported.
Assuntos
Indazóis/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Células HeLa , Humanos , Indazóis/química , Espectroscopia de Ressonância Magnética , Nootrópicos/química , Nootrópicos/farmacologia , Antagonistas da Serotonina/química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Spleen tyrosine kinase (SYK) is a critical regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compounds that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clinical evaluation in hematological malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS-9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clinical evaluation in multiple autoimmune indications.
RESUMO
As part of our continuing efforts to identify therapeutics for CNS diseases such as schizophrenia and Alzheimer's disease (AD), we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of benzoxazole derivatives as potent 5-HT(6) ligands. The synthesis and detailed SAR of this class of compounds are reported. The compounds have been shown to be full antagonists in a cyclic AMP functional assay.
Assuntos
Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Modelos Moleculares , Receptores de Serotonina/efeitos dos fármacos , Serotoninérgicos/síntese química , Benzoxazóis/química , Técnicas de Química Combinatória , AMP Cíclico/antagonistas & inibidores , Desenho de Fármacos , Ligantes , Estrutura Molecular , Serotoninérgicos/química , Serotoninérgicos/farmacologia , Relação Estrutura-AtividadeRESUMO
Cognitive dysfunction is a characteristic of various forms of dementia such as Alzheimer's disease (AD) and a core feature of schizophrenia. As part of our continuing efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor-one of the emerging therapeutic targets in this area. Herein, we report the identification of a novel series of 3-piperidinyl-5-sulfonylindazole derivatives as potent 5-HT(6) antagonists. The synthesis and SAR of this class of compounds are reported.
Assuntos
Indazóis/síntese química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Transtornos Cognitivos/tratamento farmacológico , Demência/tratamento farmacológico , Humanos , Indazóis/farmacologia , Ligantes , Piperidinas/síntese química , Piperidinas/farmacologia , Antagonistas da Serotonina/farmacologia , Ácidos Sulfínicos/síntese química , Ácidos Sulfínicos/farmacologiaRESUMO
As part of our continuing efforts to identify therapeutics for CNS diseases, such as schizophrenia and Alzheimer's disease (AD), we have been focused on the 5-HT(6) receptor in an attempt to identify ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of 1-sulfonylindazole derivatives as potent and selective 5-HT(6) antagonists. The synthesis and SAR of this class of compounds are reported. Several potent compounds in both binding and cyclase functional assays also display good selectivity, microsomal stability, solubility, and brain penetration as well as low cytochrome P450 inhibition. One compound exemplified in this series showed 24% oral bioavailability and in vivo efficacy in a NOR cognition model at 10mg/kg following an oral administration in rats.
Assuntos
Indazóis/química , Indazóis/síntese química , Receptores de Serotonina/química , Administração Oral , Animais , Disponibilidade Biológica , Doenças do Sistema Nervoso Central/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Desenho de Fármacos , Humanos , Indazóis/farmacologia , Concentração Inibidora 50 , Cinética , Ligantes , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands is reported.
Assuntos
Indóis/química , Receptores de Serotonina/química , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Ligantes , Modelos Químicos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Triptaminas/químicaRESUMO
Synthesis of 2,3-substituted indoles from phenylhydrazine and alpha-branched aldehydes via rearrangement of 3,3-disubstituted indolenine intermediates is reported. [reaction: see text]
Assuntos
Indóis/síntese química , Aldeídos/química , Catálise , Espectroscopia de Ressonância Magnética , Fenil-Hidrazinas/química , SolventesRESUMO
As part of our efforts to develop agents for CNS diseases, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for cognitive enhancement. Herein we report the identification of a novel series of 5-piperazinyl-3-sulfonylindazoles as potent and selective 5-HT(6) antagonists. The synthesis, SAR, and pharmacokinetic and pharmacological activities of some of the compounds including 3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-indazole (WAY-255315 or SAM-315) will be described.