RESUMEN
The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.
Asunto(s)
Antineoplásicos/química , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Descubrimiento de Drogas , Clorhidrato de Fingolimod , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Glicoles de Propileno/química , Glicoles de Propileno/farmacología , Ratas , Receptores de Lisoesfingolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/farmacología , Relación Estructura-ActividadRESUMEN
A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.