GDC-2394

GDC-2394 is an orally active and selective NLRP3 inhibitor, and also inhibits IL-1β with IC50s of 0.4 μM (human IL-1β) and 0.1 μM (mouse IL-1β). GDC-2394 inhibits NLRP3-induced caspase-1 activity without inhibiting NLRC4-dependent inflammasome activation[1][2].

Signaling Pathways >> Immunology/Inflammation >> Interleukin Related

Signaling Pathways >> Apoptosis >> Caspase

Research Areas >> Inflammation/Immunology

GDC-2394 (20 μM; 30 min) inhibits NLRP3-induced apoptosis associated speck-like protein containing CARD (ASC) speck formation in THP-1 cells[1]. GDC-2394 (1 nM-10 μM; 7 d) inhibits human macrophage IL-1β and IL-18 production after activation of the NLRP3 inflammasome[1]. GDC-2394 (0-20 μM; 30 min) inhibits NLRP3-dependent caspase-1 activation (IC50=51 nM) in THP-1 cells, also inhibits NLRP3-dependent IL-1β release (IC50=63 nM) and NLRC4-dependent IL-1β release (IC50>20 μM) in mouse bone marrow-derived macrophages (mBMDMs)[1].

GDC-2394 (compound 20) (1 mg/kg, 10 mg/kg; p.o.; single dose) inhibits production of IL-1β in an acute mouse peritonitis model[1]. GDC 2394 (25 mg/kg; once daily for 7 d) reduces paw swelling and pain in a functional rat model of gouty arthritis[1]. Preclinical PK of GDC-2394[1]. Species Mouse Rat Dog Cyno CLp (mL/min/kg) 10.1 1.3 11.7 4.1 Vss (L/kg) 0.72 0.29 0.67 0.18 T1/2 (h) 1.2 4.4 0.99 0.89 %F (1 mg/kg) 80 33 78 53 Animal Model: Acute mouse peritonitis model[1] Dosage: 1 mg/kg and 10 mg/kg Administration: Oral gavage; 2 h later treated with 1.25 μg LPS (i.p.) followed by 1 mg monosodium urate crystals (i.p.) a further 2 h later. Result: Resulted in a dose-dependent decrease in peritoneal IL-1β concentrations after MSU treatment, and decreased the level of IL-1β by 66.8 and 81.3% at 1 and 10 mg/kg compared with the control. Animal Model: Functional rat model of gouty arthritis[1] Dosage: 25 mg/kg Administration: Interventional injection; once daily for 7 days Result: Significantly inhibited knee swelling after 48 h.

[1]. McBride C, et al. 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. 2022 Oct 24.

[2]. Stafford, et al. Preparation of hexahydroindacenylcarbamoyldihydropyrazolooxazinesulfonamide derivatives and analogs for use as interleukin-1 activity inhibitors: World Intellectual Property Organization, WO2018136890[P]. 2018-07-26.