Overcoming preclinical safety obstacles to discover GDC-2394: A potent and selective NLRP3 inhibitor
McBride, C. et al. (2022) Overcoming preclinical safety obstacles to discover (S)‑N‑((1,2,3,5,6,7-Hexahydro‑s‑indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro‑5H‑pyrazolo[5,1‑b][1,3]oxazine-3-sulfonamide (GDC-2394): A potent and selective NLRP3 inhibitor. J. Med. Chem. DOI: 10.1021/acs.jmedchem.2c01250
Inflammasomes—multi-unit protein complexes—have become a central concept in immune system research. In particular, activation of the NLRP3 inflammasome has been widely studied, and it is implicated in variety of diseases. Accordingly, small-molecule inhibitors of NLRP3 inflammasome activation are attractive therapeutic targets.
In this study, the researchers developed a series of novel NLRP3 inhibitors targeted to minimize the risk of drug-induced liver injury observed with a well-known NLRP3 inhibitor, MCC950. Using a lipophilic ligand efficiency (LLE) strategy and starting from MCC950, the researchers developed a series of novel NLRP3 inhibitor candidates. Two candidates advanced to safety studies in nonhuman primates; however, the first lead had an inadequate solubility profile. Therefore, research efforts shifted to compound GDC-2394, which did not show adverse renal or hepatic effects in nonhuman primates. In vitro and in vivo studies with GDC-2394 demonstrated a safety profile suitable for advancing the compound into clinical trials.
Keywords: inflammasome, NLRP3, caspase-1, MCC950, NLRP3 inhibitor
