MPO-IN-1 is a powerful and orally bioavailable indole-containing inhibitor that acts irrevocably on myeloperoxidase (MPO). With IC50 values of 2.6 μM and 5.3 μM for MPO and thyroid peroxidase (TPO), respectively, MPO-IN-1 effectively inhibits both enzymes. Furthermore, it exhibits remarkable MPO inhibitory activity in an acute inflammation mouse model.

Plasma MPO assay:2.6 μM , Fluorescent MPO peroxidation assay:0.12 μM

MPO-IN-1 (compound 2), administered orally at doses of 5 and 90 mg/kg four hours after Zymosan A administration, significantly attenuates MPO activity in a male C57BL/6J mouse model of acute peritonitis, demonstrating a notable reduction in inflammation. Specifically, a 90 mg/kg dose resulted in approximately a 50% decrease in MPO activity. The pharmacokinetic profile of MPO-IN-1, including volume of distribution (Vss = 9.8 L/kg), half-life (T1/2 = 2.6 hours), area under the curve (AUCinf = 2486 nM·h) and maximum concentration (Cmax = 502 nM) after oral administration, as well as a plasma protein binding rate of 99.6%, underscores the compound’s efficacy and biodistribution characteristics.