1772-P: Novel Oral Brain Penetrant NLRP3 Inhibitor PSTC2501 for Treatment of Obesity and Cardiovascular Diseases

Introduction and Objective: NLRP3 inflammasome mediates proinflammatory cytokines (IL-1β, IL-18) secretion in response to cellular stress, and its dysregulation is linked to a spectrum of metabolic, cardiovascular, rheumatic and neurodegenerative diseases. Here, we report PSTC2501, a potent, highly selective, and brain penetrant small-molecule NLRP3 inhibitor, that potently inhibits inflammasome activation across multiple assays and exhibited high efficacy in high fat diet-induced obesity (DIO) mouse model. Methods: THP-1 cells stimulated with LPS/nigericin or LPS/ATP were used to assess IL-1β or IL-18 release for in vitro activity evaluation. The selectivity on other inflammasomes was performed in mouse BMDMs. DIO mice were used for in vivo efficacy assessment. Mice under acute LPS/ATP challenge were used for PK/PD analysis Results: PSTC2501 inhibited NLRP3 activation as measured by IL-1β or IL-18 release in THP-1 cells (IC50 between 5 - 7 nM) and showed no inhibitory effect on other inflammasomes (IC50 > 10000 nM). PSTC2501 showed consistently high CNS levels with oral dosing in mouse, rat, and dog. For in vivo studies, PSTC2501 demonstrated a robust IL-1β inhibition under acute LPS/ATP treatment. In DIO mice, PSTC2501 produced progressive and sustained weight loss, supporting the involvement of central target engagement. Co-administration of PSTC2501 with semaglutide enhanced weight loss significantly. PSTC2501 selectively reduced fat tissues with minimal reduction on lean mass. Of note, PSTC2501 demonstrated a profound decrease in inflammatory markers (e.g. fibrinogen), comparable to that reported with VTX3232. In addition, PSTC2501 mitigated fat regain after semaglutide withdrawal in a combination study. PSTC2501 was well tolerated in toxicology studies. Conclusion: This study demonstrates that PSTC2501 induces and sustains weight loss by targeting NLRP3 inflammation both centrally and peripherally. This robust anti-inflammatory effect supports its further clinical development for obese patients with cardiovascular risk.