GDC-2394

• CAT Number: I042637
• CAS Number: 2238822-07-4
• Molecular Formula: C20H25N5O4S
• Molecular Weight: 431.51
• Purity: ≥95%
• Synonyms: 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[[(6S)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl]sulfonyl]urea
• InChI: InChI=1S/C20H25N5O4S/c1-21-14-10-25-19(29-11-14)17(9-22-25)30(27,28)24-20(26)23-18-15-6-2-4-12(15)8-13-5-3-7-16(13)18/h8-9,14,21H,2-7,10-11H2,1H3,(H2,23,24,26)/t14-/m0/s1
• InChIKey: NDRARVKETDZHBS-AWEZNQCLSA-N
• SMILES: CNC1CN2C(=C(C=N2)S(=O)(=O)NC(=O)NC3=C4CCCC4=CC5=C3CCC5)OC1

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].
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

Reference

[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.
 [Content Brief]

[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.