ChemicalBook CAS DataBase List 2238822-07-4

2238822-07-4

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
Molecular Formula	C20H25N5O4S
Molecular Weight	431.51
MOL File	2238822-07-4.mol

Chemical Properties

density	1.63±0.1 g/cm3(Predicted)
form	Solid
pka	4.47±0.20(Predicted)
color	White to off-white

Hazard Information

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
CL_p (mL/min/kg)	10.1	1.3	11.7	4.1
V_ss (L/kg)	0.72	0.29	0.67	0.18
T_1/2 (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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