2. Academic Validation
  3. Discovery of NP3-742: A Structurally Diverse NLRP3 Inhibitor Identified through an Unusual Phenol Replacement

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

  • J Med Chem. 2025 Nov 13;68(21):23532-23553. doi: 10.1021/acs.jmedchem.5c02412.
Juraj Velcicky 1,  Jean-Baptiste Langlois 1,  Michael Wright 1,  Philipp Janser 1,  Daniela Angst 1,  Christelle Arnold 1,  Karen Beltz 1,  Silke Brenneisen 1,  Celine Dubois 1,  Janet Dawson 1,  Christian Fischer 1,  Nina Gommermann 1,  Andreas Heizmann 1,  Slavica Ilic 1,  Rainer Machauer 1,  Magdalena Maschlej 1,  Sarah Monnerat 1,  Daniel Pflieger 1,  Jacinda Ristov 1,  Joelle Rubert 1,  Günther Schwalm 1,  Daniel R Smith 1,  Honnappa Srinivas 1,  Roland Steiner 1,  Aleksandar Stojanovic 1,  Thomas Troxler 1,  Adeline Unterreiner 1,  Eric Vangrevelinghe 1,  Nicole von Burg 1,  Jennifer Wunderlich 1,  Christopher J Farady 1,  Angela Mackay 1
Affiliations

Affiliation

  • 1 Novartis BioMedical Research, CH-4002 Basel, Switzerland.
PMID: 41091523 DOI: 10.1021/acs.jmedchem.5c02412
Abstract

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.

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