RESUMO
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.
Assuntos
Desenho de Fármacos , Indóis/química , Receptores de Lisoesfingolipídeo/agonistas , Animais , Cães , Meia-Vida , Humanos , Indóis/síntese química , Indóis/farmacocinética , Camundongos , Ligação Proteica , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Fatores Imunológicos/química , Indóis/química , Receptores de Lisoesfingolipídeo/agonistas , Animais , Doenças Autoimunes/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Humanos , Fatores Imunológicos/farmacocinética , Fatores Imunológicos/uso terapêutico , Indóis/farmacocinética , Indóis/uso terapêutico , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Butiratos/síntese química , Butiratos/farmacologia , Imunossupressores/síntese química , Imunossupressores/farmacologia , Indóis/síntese química , Indóis/farmacologia , Linfócitos/metabolismo , Proteínas do Tecido Nervoso/agonistas , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Proteínas de Ligação a RNA/agonistas , Animais , Butiratos/farmacocinética , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Ensaios de Triagem em Larga Escala , Humanos , Imunossupressores/farmacocinética , Indóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/química , Oxidiazóis/farmacocinética , Proteínas de Ligação a RNA/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
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.
RESUMO
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.