Istradefylline-derived thienopyrimidinones give an oral NLRP3 inhibitor for colitis
- The anti-Parkinsonian drug istradefylline showed modest NLRP3 inhibition, and optimizing it gave a thienopyrimidinone series.
- Lead L22 was roughly tenfold more potent than istradefylline, bound the NLRP3 NACHT domain directly and blocked inflammasome assembly.
- It was orally bioavailable, eased symptoms in a DSS colitis model and looked safe in acute and subacute toxicity studies.
💡 Points
Starting from a marketed drug's off-target activity gives a head start on drug-likeness, and direct NACHT-domain binding is what you want to see. NLRP3 is a busy field, so the real test is how L22 compares with clinical-stage inhibitors on potency and brain or gut exposure.