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
The synthesis of two series of 4'-aza-carbocyclic nucleosides are described in which the 4'-substituent is either a reversed amide, relative to the carboxamide of NECA, or an N-bonded heterocycle. Using established purine substitution patterns, potent and selective examples of agonists of the human adenosine A(2A) receptor have been identified from both series. The propionamides 14-18 and the 4-hydroxymethylpyrazole 32 were determined to be the most potent and selective examples from the 4'-reversed amide and 4'-N-bonded heterocyclic series, respectively.