RESUMO
Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio/química , Indóis/química , Piridinas/química , Pirróis/química , Animais , Asma , Compostos Aza/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Indóis/farmacocinética , Indóis/uso terapêutico , Interleucina-2/sangue , Interleucina-2/metabolismo , Células Jurkat , Microssomos/metabolismo , Modelos Biológicos , Ovalbumina/imunologia , Ligação Proteica , Piridinas/farmacocinética , Piridinas/uso terapêutico , Pirróis/farmacocinética , Pirróis/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
Previously we have described a novel series of potent and selective A 2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A 2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.
Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Antagonistas do Receptor A2 de Adenosina , Pirimidinas/síntese química , Pirimidinas/farmacologia , Acetamidas/química , Animais , Sítios de Ligação , Ciclização , Avaliação Pré-Clínica de Medicamentos , Hepatócitos/efeitos dos fármacos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirimidinas/química , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.
Assuntos
Acetamidas/farmacologia , Antagonistas do Receptor A2 de Adenosina , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Pirimidinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Antagonistas do Receptor A1 de Adenosina , Animais , Avaliação Pré-Clínica de Medicamentos , Canais de Potássio Éter-A-Go-Go/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Wistar , Especificidade da Espécie , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Antiparkinsonianos/síntese química , Catalepsia/prevenção & controle , Doença de Parkinson/fisiopatologia , Fenoxiacetatos/síntese química , Pirimidinas/síntese química , Administração Oral , Animais , Antiparkinsonianos/farmacologia , Catalepsia/induzido quimicamente , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Eletrofisiologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Haloperidol/toxicidade , Humanos , Estrutura Molecular , Fenoxiacetatos/química , Fenoxiacetatos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Proteínas de Ligação a DNA/antagonistas & inibidores , Pirimidinas/farmacologia , Transativadores/antagonistas & inibidores , Linhagem Celular , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Desenho de Fármacos , Humanos , Cinética , Pirimidinas/síntese química , Pirimidinas/química , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-Atividade , Regulador Transcricional ERGRESUMO
Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.