RESUMEN
Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor.
Asunto(s)
Diseño de Fármacos , Indoles/química , Receptores de Lisoesfingolípidos/agonistas , Animales , Perros , Semivida , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Ratones , Unión Proteica , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Lisoesfingolípidos/metabolismo , Relación Estructura-ActividadRESUMEN
APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.
RESUMEN
S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties.
RESUMEN
Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat.
Asunto(s)
Factores Inmunológicos/química , Indoles/química , Receptores de Lisoesfingolípidos/agonistas , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Humanos , Factores Inmunológicos/farmacocinética , Factores Inmunológicos/uso terapéutico , Indoles/farmacocinética , Indoles/uso terapéutico , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Lisoesfingolípidos/metabolismo , Relación Estructura-ActividadRESUMEN
S1P(1) receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P(1) receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P(1) receptor agonists.
