RESUMO
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
Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Analgésicos/química , Animais , Encéfalo/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Química Combinatória , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estrutura Molecular , Medição da Dor , Pirazóis/química , Ratos , Receptores de Prostaglandina E Subtipo EP1 , Relação Estrutura-AtividadeRESUMO
High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.
