RESUMO
We describe the SAR, in terms of heterocyclic replacements, for a series of pyrazole EP(1) receptor antagonists. This study led to the identification of several aromatic heterocyclic replacements for the pyrazole in the original compound. Investigation of replacements for the methylene linker uncovered disparate SAR in the thiazole and pyridine series.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Receptores de Prostaglandina E Subtipo EP1 , 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
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
We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Técnicas In Vitro , Ratos , Receptores de Prostaglandina E Subtipo EP1RESUMO
Starting from the tetrapeptide Ac-pYEEI-NHMe and using a structure-based approach, we have designed and synthesised a peptidomimetic ligand for p56(lck) SH2 domain containing a conformationally restricted replacement for the two glutamate residues. We have explored replacments for the isoleucine residue in the pY+3 pocket and thus identified 1-(R)-amino-3-(S)-indaneacetic acid as the most potent replacement. We also report the X-ray crystal structures of two of the antagonists.