Pyridazino-indoles replace the phenol in pyridazine NLRP3 inhibitors
- Indole-fused pyridazines were developed to replace the phenol group of earlier phenol-pyridazine NLRP3 inhibitors.
- Cryo-EM and modeling suggest the indole keeps the key contact with Ala228 in the binding site.
- Two lead compounds reached low-nanomolar potency with good solubility and permeability, and were profiled in mouse pharmacokinetic studies.
- hERG inhibition ended development, though the compounds remain useful in vivo tools; a reactive metabolite audit is also reported.
💡 Points
Replacing the phenol with an indole-fused pyridazine removes phenol liabilities while keeping the Ala228 contact, and potency and solubility look healthy. The cautionary note is hERG ending a series this strong: did the flat, lipophilic fused ring cause it? I would treat these compounds as in vivo tools, not a template to copy without scrutiny.
Pyridazino-Indoles as Phenol Bioisosteres for Potent Inhibition of NLRP3 ↗