Discovery of NP3-742: A Structurally Diverse NLRP3 Inhibitor Identified through an Unusual Phenol Replacement

NLRP3 is a molecular sensor present in innate immune
cells which
recognizes a variety of danger signals such as MSU, ATP, or Aβ.
Upon activation, it seeds a protein complex termed the inflammasome,
which leads to secretion of the proinflammatory cytokines IL-1β
and IL-18 and initiates pyroptotic cell death. NLRP3 inflammasome
activation has been associated with a wide range of diseases including
atherosclerosis, gout, and cancer. In this publication, we describe
the replacement of the phenol moiety with indoles in the recently
described pyridazine scaffold. This replacement required a shift of
the hydrogen bond donor from the “ortho”
to the “meta” position, relative to
the pyridazine ring. Initial indole analog 7 demonstrated
a robust in vivo IL-1β inhibition, but also a significant hERG
inhibition. Decreasing lipophilicity led to the discovery of NP3-742, demonstrating a favorable overall profile including
diminished hERG inhibition and in vivo efficacy in a mouse peritonitis
model.