RESUMEN
In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.
Asunto(s)
Corticoesteroides/síntesis química , Corticoesteroides/farmacocinética , Antiasmáticos/síntesis química , Antiasmáticos/farmacocinética , Asma/tratamiento farmacológico , Diseño de Fármacos , Administración por Inhalación , Corticoesteroides/administración & dosificación , Corticoesteroides/farmacología , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/uso terapéutico , Androstadienos/química , Androstadienos/farmacología , Animales , Antiasmáticos/administración & dosificación , Antiasmáticos/farmacología , Asma/epidemiología , Asma/fisiopatología , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Inhaladores de Polvo Seco , Fluticasona , Hepatocitos , Humanos , Hígado , Pulmón , Microsomas Hepáticos , Neutrófilos/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Ratas , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/sangreRESUMEN
A series of libraries were designed using the 1-(cyclopropylmethyl)-2-alkyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5-ium templates 2a-b, and Sulfonamide derivatives 11a-n proved to be potent agonists of the CB(2) receptor. Analysis of the Lipophilic Efficiency (LipE) of potent compounds provided new insight for the design of potent, metabolically stable CB2 agonists.