RESUMO
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Assuntos
Acetamidas/uso terapêutico , Antagonistas de Receptor B1 da Bradicinina , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Piperazinas/uso terapêutico , Acetamidas/síntese química , Acetamidas/química , Animais , Cães , Concentração Inibidora 50 , Camundongos , Modelos Animais , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Coelhos , Ratos , Receptor B1 da Bradicinina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The bradykinin 1 (B1) receptor is upregulated during times of inflammation and is important for maintaining inflamed and chronic pain states. Blocking this receptor has been shown to reverse and/or ameliorate pain and inflammation in animal models. In this report, we describe a new class of B1 receptor antagonists that contain the piperidine acetic acid tetralin core. A structure-activity relationship for these analogs is described in this paper. The most potent compounds from this class have IC50s<20 nM in a B1 receptor functional assay. One of these compounds, 13g, shows modest oral bioavailability in rats.