Drug Metabolism and Pharmacokinetics of Oxazolo[4,5-c]quinoline Analogs as Novel Interleukin-33 Inhibitors.

Abstract

Background/Objectives: Interleukin-33 (IL-33) is crucial in immune-mediated diseases like asthma. Targeting the IL-33/ST2 pathway holds therapeutic promise. This study characterized the pharmacokinetics (PK) and metabolism of KB-1517 and KB-1518, new oxazolo[4,5-c]quinoline IL-33 inhibitors. Methods: PK studies were conducted in male ICR mice following intravenous (IV) and oral (PO) administration. In vitro metabolic stability and metabolite identification were assessed using human and mouse liver S9 fractions supplemented with cofactors (NADPH, UDPGA, PAPS, GSH). Plasma and incubation samples were analyzed using validated LC-MS/MS methods. Results: KB-1517 exhibited slow absorption/elimination and high apparent oral bioavailability (>100%) post-PO, with an unusually late increase in plasma concentration after IV dosing, hindering terminal parameter calculation. KB-1518 showed low clearance post-IV but suffered from low oral bioavailability (~14%). Both compounds demonstrated high in vitro metabolic stability (t_½ > 60 min) in both human and mouse liver S9 fractions. Primary metabolism involved phase I oxidation (N-oxidation and N-demethylation), yielding several metabolites identified in vitro and confirmed in vivo. Some species differences in metabolite profiles were observed. Conclusions: KB-1517 and KB-1518 are promising, metabolically stable IL-33 inhibitor lead compounds with distinct PK profiles. KB-1517's complex kinetics suggest potential sustained exposure but require further elucidation. KB-1518's low oral bioavailability necessitates further optimization. These ADME findings provide a critical foundation for their continued optimization and development.