Andreas Holmqvist

Discovery of NP3-253, a Potent Brain Penetrant Inhibitor of the NLRP3 Inflammasome Activation of the NLRP3 inflammasome in response to danger signals is a key innate immune mechanism and results in the production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as pyroptotic cell death. Aberrant NLRP3 activation has been linked to many acute and chronic conditions ranging from atherosclerosis to Alzheimer’s disease and cancer, and based on the clinical success of IL-1-targeting therapies, NLRP3 has emerged as an attractive therapeutic target. Herein we describe our discovery, characterization, and structure-based optimization of a pyridazine-based series of NLRP3 inhibitors initiating from an high-throughput screening campaign. The scaffold, exemplified by lead molecule NP3-253, has excellent potency and physicochemical and pharmacokinetic properties, including good brain penetration. The establishment of pharmacokinetic/pharmacodynamic relationships in the periphery and central nervous system in mechanistic models facilitates the use of NP3-253 as a tool to further interrogate the biology of NLRP3 in peripheral and neuroinflammatory models.

Very interesting paper of a CNS-penetrant NLRP3 inhibitor discovery by @novartis.bsky.social! 🧠 Interestingly, alkylation of the phenol increased the MDCK-MDR1 ER, suggesting reduced brain penetration, an unexpected twist in their optimization journey!
pubs.acs.org/doi/10.1021/...
#DrugDiscovery

One-Step Regioselective Synthesis of N-1-Substituted Dihydrouracils: A Motif of Growing Popularity in the Targeted Protein Degradation Field The increasing popularity of the dihydrouracil motif in cereblon (CRBN) recruiting proteolysis-targeting chimeras (PROTACs) has necessitated the development of a facile, cost-effective, and high-yield...

Very handy paper for chemists working on CRBN based PROTACS 👊
#PROTAC #TPD #Cereblon

doi.org/10.1021/acs....