RESUMO
The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P2.
Assuntos
Derivados de Benzeno/química , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Administração Oral , Animais , Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacocinética , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Haplorrinos , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratos , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Esfingosina-1-Fosfato , Relação Estrutura-AtividadeRESUMO
Our initial lead compound 2 was modified to improve its metabolic stability. The resulting compound 5 showed excellent metabolic stability in rat and human liver microsomes. We subsequently designed and synthesized a hybrid compound of 5 and the 1,3-bis(aryloxy) benzene derivative 1, which was previously reported by our group to be an S1P2 antagonist. This hybridization reaction gave compound 9, which showed improved S1P2 antagonist activity and good metabolic stability. The subsequent introduction of a carboxylic acid moiety into 9 resulted in 14, which showed potent antagonist activity towards S1P2 with a much smaller species difference between human S1P2 and rat S1P2. Compound 14 also showed good metabolic stability and an improved safety profile compared with compound 9.
Assuntos
Derivados de Benzeno/farmacologia , Descoberta de Drogas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Animais , Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Ratos , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Esfingosina-1-Fosfato , Relação Estrutura-AtividadeRESUMO
The structure-activity relationships of a novel series of sphingosine-1-phosphate receptor antagonists have been examined in detail. The initial hit compound 1 was modified through synthesis to improve its S1P2 activity. The synthesis of a series of analogs revealed that 1,3-bis(aryloxy)benzene derivatives, as represented by 22, are potent and selective S1P2 antagonists.