Discovery of PIPE-791, A Potent and Brain-Penetrant Lysophosphatidic Acid Receptor 1 Antagonist with Slow Tight Binding Characteristics for the Treatment of Neuroinflammatory Disorders

We describe the discovery and characterization of PIPE-791, a potent and brain-penetrant lysophosphatidic acid receptor 1 (LPAR1) antagonist with slow association and dissociation kinetics. SAR studies initiated from a literature lead (13) led to the identification of compound 21 that possessed a unique urea scaffold responsible for slow but tight binding to LPAR1. Further optimizations that improved PK and metabolic profiles led to the discovery of PIPE-791. PIPE-791 efficiently traversed the BBB in multiple preclinical species and was efficacious in preclinical models of neuroinflammatory disorders. PIPE-791 possessed excellent ADME properties and was well-tolerated in 28 day GLP (Good Laboratory Practice) toxicity studies in rats and minipigs at doses up to 1000 mg/kg/day. Based on these results and a comprehensive first-in-human enabling preclinical data package, PIPE-791 was advanced into clinical development, including an ongoing trial in subjects with chronic osteoarthritis pain or chronic lower back pain (NCT6810245).