1.
Bioorg Med Chem
; 21(21): 6582-91, 2013 Nov 01.
Artículo
en Inglés
| MEDLINE
| ID: mdl-24021582
RESUMEN
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.
Asunto(s)
Indolizinas/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Animales , Células CHO , Cricetinae , Cricetulus , Dermatitis por Contacto/tratamiento farmacológico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Semivida , Humanos , Hipersensibilidad/tratamiento farmacológico , Indolizinas/farmacocinética , Indolizinas/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Relación Estructura-Actividad , Células Th2/inmunología , Células Th2/metabolismo
2.
Bioorg Med Chem Lett
; 17(15): 4347-50, 2007 Aug 01.
Artículo
en Inglés
| MEDLINE
| ID: mdl-17531480
RESUMEN
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.