RESUMEN
Glucocorticoids are used widely in the treatment of inflammatory diseases, but use is accompanied by a significant burden of adverse effects. It has been hypothesized that gene- and cell-specific regulation of the glucocorticoid receptor by small molecule ligands could be translated into a therapeutic with an improved risk-benefit profile. MK-5932 is a highly selective glucocorticoid receptor modulator that is anti-inflammatory in vivo with an improved profile on glucose metabolism: Bungard et al. (2011). Bioorg. Med. Chem. 19, 7374-7386. Here we describe the full biological profile of MK-5932. Cytokine production following lipopolysaccharide (LPS) challenge was blocked by MK-5932 in both rat and human whole blood. Oral administration reduced inflammatory cytokine levels in the serum of rats challenged with LPS. MK-5932 was anti-inflammatory in a rat contact dermatitis model, but was differentiated from 6-methylprednisolone by a lack of elevation of fasting insulin or glucose levels after 7 days of dosing, even at high exposure levels. In fact, animals in the vehicle group were consistently hyperglycemic at the end of the study, and MK-5932 normalized glucose levels in a dose-dependent manner. MK-5932 was also anti-inflammatory in the rat collagen-induced arthritis and adjuvant-induced arthritis models. In healthy dogs, oral administration of MK-5932 exerted acute pharmacodynamic effects with potency comparable to prednisone, but with important differences on neutrophil counts, again suggestive of a dissociated profile. Important gaps in our understanding of mechanism of action remain, but MK-5932 will be a useful tool in dissecting the mechanisms of glucose dysregulation by therapeutic glucocortiocids.
Asunto(s)
Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Benzamidas/uso terapéutico , Dermatitis por Contacto/tratamiento farmacológico , Edema/tratamiento farmacológico , Indazoles/uso terapéutico , Receptores de Glucocorticoides/metabolismo , Animales , Antiinflamatorios/sangre , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Benzamidas/sangre , Benzamidas/farmacocinética , Benzamidas/farmacología , Línea Celular Tumoral , Colágeno , Citocinas/sangre , Perros , Femenino , Células HeLa , Humanos , Indazoles/sangre , Indazoles/farmacocinética , Indazoles/farmacología , Insulina , Lipopolisacáridos , Masculino , Metilprednisolona/farmacología , Ratas , Ratas Endogámicas Lew , Ratas Sprague-DawleyRESUMEN
The novel T-type antagonist ( S)- 5 has been prepared and evaluated in in vitro and in vivo assays for T-type calcium ion channel activity. Structural modification of the piperidine leads 1 and 2 afforded the fluorinated piperidine ( S)- 5, a potent and selective antagonist that displayed in vivo CNS efficacy without adverse cardiovascular effects.