Physicochemical Characterization, Metabolite Profiling, and Preclinical Pharmacokinetic Assessment of a Sulfonamide-Based Pyruvate Kinase M2 Activator for Anticancer Lead Identification

Abstract

This study investigates the pharmacokinetic, physicochemical, and metabolite properties of 9b, a novel imidazopyrimidine-based sulfonamide previously shown to be effective against the A549 lung adenocarcinoma cell line. Aiming to evaluate its ADME (absorption, distribution, metabolism, and excretion) characteristics for drug development, the study found that 9b possesses favorable physicochemical properties, including a pKa of 12.35, LogP of 2.89, and LogD of 0.98. Stability tests demonstrated that 9b remains stable in human plasma and liver microsomes for up to 1 h, with moderate plasma protein binding (46%). Metabolite profiling using LC/Q-TOF MS revealed three major metabolites (M1, M2, and M3), whereas in vivo pharmacokinetic analysis via LC/QQQ-MS indicated optimal pharmacokinetic parameters, including C_max, T_max, AUC, and a half-life (t_1/2) consistent with a balanced pharmacokinetic profile. These results highlight 9b’s promising stability, moderate protein binding, and favorable metabolic profile, positioning it as a strong candidate for further development as an anticancer drug. Given its impressive pharmacokinetic properties and demonstrated efficacy in cancer cell lines, 9b shows significant potential for advancing cancer treatment.