| Identification | Back Directory | [Name]
5H-Pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide, N-[[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino]carbonyl]-6,7-dihydro-6-(methylamino)-, (6S)- | [CAS]
2238822-07-4 | [Synonyms]
5H-Pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide, N-[[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino]carbonyl]-6,7-dihydro-6-(methylamino)-, (6S)- | [Molecular Formula]
C20H25N5O4S | [MOL File]
2238822-07-4.mol | [Molecular Weight]
431.51 |
| Hazard Information | Back Directory | [Description]
GDC-2394 is a A Potent and Selective NLRP3 Inhibitor with an in vitro and in vivo safety profile suitable for advancement into human clinical trials. GDC 2394 Inhibits In Vivo Production of IL-1β in an Acute Mouse Peritonitis Model. GDC 2394 Reduces Paw Swelling and Pain in a Functional Rat Model of Gouty Arthritis. | [Uses]
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]. | [in vivo]
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. |
| [References]
[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. DOI:10.1021/acs.jmedchem.2c01250
[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. |
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