RESUMEN
Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.
Asunto(s)
Isoxazoles/síntesis química , Isoxazoles/farmacología , Lisofosfolípidos/agonistas , Esfingosina/análogos & derivados , Animales , Artritis Experimental/tratamiento farmacológico , Células CHO , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cricetinae , Cricetulus , Descubrimiento de Drogas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Sistema Linfático/citología , Sistema Linfático/efectos de los fármacos , Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Endogámicas Lew , Esfingosina/agonistas , Relación Estructura-Actividad , Timo/citología , Timo/efectos de los fármacosRESUMEN
Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.