Pyridazino-Indoles as Phenol Bioisosteres for Potent Inhibition of NLRP3

Aberrant activation of the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome drives chronic diseases, necessitating robust therapeutic inhibitors. Despite the promise of phenol-based pyridazines, we sought to evaluate the possibility of replacing the phenol moiety. This article presents the medicinal chemistry efforts leading to the discovery of pyridazino-indoles as potent phenol bioisosteres. These findings are based upon prior work, initially and to the best of our knowledge first disclosed in our Roche patent application published in 2023. Using cryo-EM and molecular modeling, we rationalized the binding mode, ensuring the indole scaffold maintained critical interactions, specifically with Ala228. The resulting lead indole compounds, 13 and 15, achieved single-digit nanomolar potency with excellent solubility, permeability and were profiled in mouse in vivo PK studies. Although hERG inhibition was identified as a safety concern and a reason for discontinuing their development, these novel indoles remain high-quality in vivo tool compounds. We report here the first comprehensive safety audit of the pyridazino-indoles, mapping reactive metabolite pathways.