| In Vitro | In vitro activity: DprE1-IN-1, a 1,4-azaindole analog, is a potent inhibitor of decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1) with ic50 of 10 nM; it also inhibits PDE6 with IC50 of 6 uM. It demonstrats efficacy in a rodent model of tuberculosis, making it promising for further development. DprE1-IN-1 has excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. In summary, DprE1-IN-1 is a promising candidate for the development of a novel anti-TB drug.
Kinase Assay: DprE1-IN-1, a 1,4-azaindole analog, is a potent inhibitor of decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1) with ic50 of 10 nM; it also inhibits PDE6 with IC50 of 6 uM. |
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| In Vivo | DprE1-IN-1 demonstrats efficacy in a rodent model of tuberculosis, making it promising for further development. The pharmacokinetic profile of DprE1-IN-1 as a representative of the series in mice, rats, and dogs was determined after i.v. and oral dosing. DprE1-IN-1 shows oral bioavailabilities of 86% and 100% in rats and dogs, respectively. The oral exposures of DprE1-IN-1, assessed in infected animals, shows AUCs ranging from 166 to 240 μM · h, and free plasma concentrations were maintained above the MIC for 10 to 24 h. |
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