RESUMO
In pursuit of potent and selective sphingosine-1-phosphate receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.
Assuntos
Amidas/síntese química , Imidazóis/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Amidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Cloridrato de Fingolimode , Imidazóis/farmacologia , Camundongos , Propilenoglicóis/química , Propilenoglicóis/farmacologia , Subunidades Proteicas/agonistas , Subunidades Proteicas/fisiologia , Receptores de Lisoesfingolipídeo/fisiologia , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/farmacologiaRESUMO
In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.
