Preclinical Pharmacokinetics, ADME, and Drug-Drug Interaction Evaluation of S024, a Novel p38/MK2 Inhibitor for Rheumatoid Arthritis

Introduction: S024 is a novel dual p38/MK2 inhibitor with therapeutic potential for rheumatoid arthritis (RA). Unlike existing RA therapies often limited by suboptimal efficacy and safety profiles, S024 selectively targets the p38/MK2 signaling complex, representing a mechanistically distinct treatment strategy. This study aimed to systematically characterize the preclinical pharmacokinetic (PK), absorption, distribution, metabolism, excretion (ADME), and drug-drug interaction (DDI) profiles of S024. Methods: Permeability was assessed using Caco-2 cell monolayers. PK and oral bioavailability were determined in Sprague-Dawley (SD) rats and beagle dogs. Plasma protein binding (PPB), tissue distribution, in vitro metabolic stability (across species), enzyme phenotyping, excretion mass balance, and DDI potential against major CYP450 enzymes and key ABC/SLC transporters were comprehensively evaluated. Results: S024 displayed low permeability in Caco-2 assays, likely attributable to P-gp-mediated efflux. Despite this, oral absorption remained efficient, with high bioavailability in rats (F%=56.3~101%) and dogs (F%=40.1~110%). S024 exhibited moderate PPB across species and minimal red blood cell distribution. Extensive tissue distribution was observed in rats, predominantly in the gastrointestinal tract and well-perfused organs. Hepatic clearance varied significantly across species, with values of 320.9, 43.8, < 25.6, 25.7, and < 10.3 mL/min/kg in mice, rats, dogs, monkeys, and humans, respectively. CYP2C8 and CYP3A were identified as the primary metabolic enzymes. Excretion studies confirmed that S024 was eliminated predominantly as metabolites via feces. DDI profiling revealed only modest inhibition of CYP2C8 (IC 5 0 = 77.2 μM) and weak induction of CYP3A4 mRNA at 10 μM without corresponding enzymatic activity increase. Minimal inhibitory potency was observed against key ABC and SLC transporters, with IC 5 0 values generally exceeding predicted therapeutic concentrations. Conclusion: S024 demonstrated favorable preclinical PK/ADME properties, characterized by robust oral absorption, moderate PPB, extensive distribution, and a low predicted clinical DDI risk. These findings strongly support its further development as a promising clinical candidate for RA therapy. Keywords: S024, p38/MK2 inhibitor, pharmacokinetics, ADME profiling, rheumatoid arthritis