RESUMEN
Structure-activity relationships of 6-(benzoylamino)benzoxaborole analogs were investigated for the inhibition of TNF-α, IL-1ß, and IL-6 from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compound 1q showed potent activity against all three cytokines with IC50 values between 0.19 and 0.50µM, inhibited LPS-induced TNF-α and IL-6 elevation in mice and improved collagen-induced arthritis in mice. Compound 1q (AN4161) is considered to be a promising lead for novel anti-inflammatory agent with an excellent pharmacokinetic profile.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Derivados del Benceno/química , Derivados del Benceno/uso terapéutico , Compuestos de Boro/química , Compuestos de Boro/uso terapéutico , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Derivados del Benceno/farmacocinética , Derivados del Benceno/farmacología , Compuestos de Boro/farmacocinética , Compuestos de Boro/farmacología , Interleucina-1beta/inmunología , Interleucina-6/inmunología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Lipopolisacáridos/inmunología , Ratones , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Human African trypanosomiasis, caused by the kinetoplastid parasite Trypanosoma brucei, affects thousands of people across sub-Saharan Africa, and is fatal if left untreated. Treatment options for this disease, particularly stage 2 disease, which occurs after parasites have infected brain tissue, are limited due to inadequate efficacy, toxicity and the complexity of treatment regimens. We have discovered and optimized a series of benzoxaborole-6-carboxamides to provide trypanocidal compounds that are orally active in murine models of human African trypanosomiasis. A key feature of this series is the presence of a boron atom in the heterocyclic core structure, which is essential to the observed trypanocidal activity. We also report the in vivo pharmacokinetic properties of lead compounds from the series and selection of SCYX-7158 as a preclinical candidate.