RESUMO
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.].
RESUMO
Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.
RESUMO
Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.
Assuntos
Indolizinas/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Dermatite de Contato/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Meia-Vida , Humanos , Hipersensibilidade/tratamento farmacológico , Indolizinas/farmacocinética , Indolizinas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Relação Estrutura-Atividade , Células Th2/imunologia , Células Th2/metabolismoRESUMO
High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat.
Assuntos
Acetatos/química , Anti-Inflamatórios/química , Piridinas/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Acetatos/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Humanos , Microssomos Hepáticos/metabolismo , Permeabilidade , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.