RESUMEN
The heterodimeric transmembrane αv integrin receptors have recently emerged as potential targets for the treatment of idiopathic pulmonary fibrosis. Herein, we describe how subtle modifications of the central aromatic ring of a series of phenylbutyrate-based antagonists of the vitronectin receptors αvß3 and αvß5 significantly change the biological activities against αvß6 and αvß8. This resulted in the discovery of a pan αv antagonist (compound 39, 4-40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with a clearance of 7.6 mL/(min kg) and a bioavailability of 97%).
Asunto(s)
Fibrosis Pulmonar Idiopática/patología , Integrina alfaV/química , Fenilbutiratos/química , Administración Oral , Animales , Antígenos de Neoplasias/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/metabolismo , Integrina alfaV/metabolismo , Integrina alfaVbeta3/antagonistas & inhibidores , Integrina alfaVbeta3/metabolismo , Integrinas/antagonistas & inhibidores , Integrinas/metabolismo , Conformación Molecular , Simulación del Acoplamiento Molecular , Fenilbutiratos/farmacocinética , Fenilbutiratos/uso terapéutico , Estructura Terciaria de Proteína , Ratas , Receptores de Vitronectina/antagonistas & inhibidores , Receptores de Vitronectina/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology.
Asunto(s)
Indazoles/química , Receptores de Glucocorticoides/agonistas , Sulfonamidas/síntesis química , Sitios de Unión , Línea Celular Tumoral , Simulación por Computador , Evaluación Preclínica de Medicamentos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Indazoles/síntesis química , Indazoles/farmacología , Receptores de Glucocorticoides/metabolismo , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NFkappaB pIC(50) 8.1 (103%), MMTV pEC(50) 7.02 (36%)). The tetrahydronaphthalene moiety can also be replaced with substituted aryls such as 24E1 and 25E1.