RESUMO
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.
Assuntos
Anti-Inflamatórios não Esteroides/química , Benzofuranos/química , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/uso terapêutico , Benzofuranos/farmacocinética , Benzofuranos/uso terapêutico , Linhagem Celular , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Dor/tratamento farmacológico , Ratos , Receptores de Prostaglandina E Subtipo EP1/metabolismo , Relação Estrutura-AtividadeRESUMO
We describe the discovery of a series of pyrazole amide EP(1) receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1-2.0:1 in addition to good solubility and metabolic stability.
Assuntos
Encéfalo/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Pirazóis/química , Receptores de Prostaglandina E/antagonistas & inibidores , Amidas/química , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Isoquinolinas/química , Modelos Químicos , Estrutura Molecular , Receptores de Prostaglandina E Subtipo EP1 , Solubilidade , Relação Estrutura-AtividadeRESUMO
A novel series of oxadiazole EP1 receptor antagonists was identified by replacing the amide of a known glycine sulfonamide derivative with a 1,3,4-oxadiazole. Optimization of the substitution patterns on the three aromatic rings led to the identification of high affinity EP1 receptor antagonists. The derivative with highest affinity displayed a binding IC50 of 2.5 nM (pIC50 8.6).
Assuntos
Oxidiazóis/química , Oxidiazóis/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.
Assuntos
Analgésicos/síntese química , Dor/tratamento farmacológico , Piranos/síntese química , Pirimidinas/síntese química , Receptor CB2 de Canabinoide/agonistas , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Meia-Vida , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Dor/metabolismo , Piranos/farmacocinética , Piranos/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects.