RESUMO
In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed.
Assuntos
Acetamidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Piperazinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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
Recent years have seen the rapid advancement of new therapeutic agents against hepatitis C virus (HCV) in response to the need for treatment that is unmet by interferon (IFN)-based therapies. Most antiviral drugs discovered to date are small molecules that modulate viral enzyme activities. In the search for highly selective protein-binding molecules capable of disrupting the viral life cycle, we have identified a class of anionic tetraphenylporphyrins as potent and specific inhibitors of the HCV replicons. Based on the structure-activity relationship studies reported herein, meso-tetrakis-(3,5-dicarboxy-4,4'-biphenyl) porphyrin was found to be the most potent inhibitor of HCV genotype 1b (Con1) replicon systems but was less effective against the genotype 2a (JFH-1) replicon. This compound induced a reduction of viral RNA and protein levels when acting in the low nanomolar range. Moreover, the compound could suppress replicon rebound in drug-treated cells and exhibited additive to synergistic effects when combined with protease inhibitor BILN 2061 or with IFN-alpha-2a. Our results demonstrate the potential use of tetracarboxyphenylporphyrins as potent anti-HCV agents.
Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Mesoporfirinas/química , Mesoporfirinas/farmacologia , Carbamatos/farmacologia , Linhagem Celular , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/genética , Relação Dose-Resposta a Droga , Descoberta de Drogas , Farmacorresistência Viral , Sinergismo Farmacológico , Genótipo , Humanos , Interferon alfa-2 , Interferon-alfa/farmacologia , Compostos Macrocíclicos/farmacologia , Quinolinas/farmacologia , RNA Viral/efeitos dos fármacos , RNA Viral/genética , Proteínas Recombinantes , Replicon , Relação Estrutura-Atividade , Tiazóis/farmacologia , Proteínas não Estruturais Virais/efeitos dos fármacos , Proteínas não Estruturais Virais/genéticaRESUMO
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Dor/tratamento farmacológico , Sulfonas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Antagonistas de Receptor B2 da Bradicinina , Doença Crônica , Humanos , Coelhos , Ratos , Ratos Sprague-Dawley , Sulfonas/administração & dosagemRESUMO
A family of tetrabiphenylporphyrin-based receptors has been synthesized. Receptor 7 showed sub-nanomolar affinity (K(d)=0.67 nM) in binding to the surface of cytochrome c. In addition, a stoichiometric amount of the receptor 7 caused a lowering in the T(m) of cytochrome c from 85 to 35 degrees C.