DprE1-IN-4

DprE1-IN-4 is a potent and orally active noncovalent DprE1 inhibitor with an IC50 of 0.90 μg/mL. DprE1-IN-4 exhibits potent in vitro activity against M. tuberculosis H37Rv and drug-resistant tuberculosis strain with MIC values of 0.12 μg/mL and 0.24 μg/mL, respectively. DprE1-IN-4 displays acceptable pharmacokinetic property and shows significant bactericidal activity in an acute mouse model of tuberculosis[1].

Research Areas >> Infection

Signaling Pathways >> Anti-infection >> Bacterial

IC50: 0.9±0.2 μg/mL (DprE1)[1]

DprE1-IN-4 displays potent activity against M. tuberculosis, it is against isolated clinical strains H37Rv, 13946a, 14862b and PBTZ169-resistant strain with MIC values of 0.12 μg/mL, 0.24 μg/mL, 0.24 μg/mL and 0.48 μg/mL, respectively[1]. DprE1-IN-4 (0.76-16 μg/mL) shows a decrease in potency against only DprE1-overexpressing strains but not against DprE2-overexpressing and wild-type strains. The IC50 value is 0.9±0.2 μg/mL for  DprE1[1].

DprE1-IN-4 exhibits acceptable pharmacokinetic property after p.o. and i.v., DprE1-IN-4 (oral administration, 50 mg/kg) exhibits high plasma exposure ((AUC)0-∞=657 ng·h/mL) and high maximum plasma concentration (Cmax=486 ng/mL). It exhibits oral bioavailability (F=7.9%) and is deemed worthy of further evaluation in in vivo efficacy studies[1]. DprE1-IN-4 (oral gavage; 100 mg/kg; once daily; 3 weeks) showed potent in vivo activity, reducing the bacterial burden in the lungs by 2.02 log10 CFU compared with the untreated control group[1].

[1]. Pengxu Wang, et al. Discovery of Novel Thiophene-arylamide Derivatives as DprE1 Inhibitors with Potent Antimycobacterial Activities. J Med Chem. 2021 May 13;64(9):6241-6261.