CY-09

CY-09 specifically blocks NLRP3 activation in macrophages. This compound inhibits NLRP3 oligomerization and inflammasome assembly. It directly binds to NLRP3 and inhibits its ATPase activity. The metabolic stability of this chemical was first evaluated using human and mouse liver microsomes, exhibiting favorable stability with the half-life >145 min for both human and mouse microsomes. The metabolic stability of this compound was first evaluated using human and mouse liver microsomes, exhibiting favorable stability with the half-life >145 min for both human and mouse microsomes, which exhibited low risk of drug-drug interactions[1].

CY-09 inhibits NLRP3 activation in vivo and prevents neonatal lethality in a mouse model of CAPS. In pharmacokinetic studies evaluted in C57BL/6J mice administered a single i.v. or oral dose, this compound exhibits favorable pharmacokinetics, with a half-life of 2.4 h, an area under the curve of 8,232 (h·ng)/ml, and bioavailability of 72%. It reverses metabolic disorders in diabetic mice by inhibition of NLRP3-dependent inflammation. This chemical treatment has remarkable beneficial effects for metainflammation, hyperglycemia, and insulin resistance in diabetic mice[1].

• 세포주

  BMDMs and PBMCs

• 농도

  1, 5, and 10 μM

• 배양 시간

  30 min

• 방법

  5 × 10⁵/ml BMDMs and 6 × 10⁶/ml PBMCs were plated in 12-well plates. The following morning, the medium was replaced, and cells were stimulated with 50 ng/ml LPS or 400 ng/ml Pam3CSK4 (for noncanonical inflammasome activation) for 3 h. After that, CY-09 or other inhibitors were added into the culture for another 30 min, and then the cells were stimulated for 4 h with MSU (150 µg/ml), Salmonella typhimurium (multiplicity of infection) or for 30 min with ATP (2.5 mM) or nigericin (10 µM). Cells were transfected with poly(dA:dT) (0.5 µg/ml) for 4 h or LPS (500 ng/ml) overnight. Cell extracts and precipitated supernatants were analyzed by immunoblot.

• 동물 모델

  C57BL/6J mice

• 용량

  5 and 10 mg/kg

• 투여

  i.v. and oral administration