HPGDS inhibitor 3

HPGDS inhibitor 3 is an orally active and highly potent peripherally restricted hematopoietic prostaglandin D synthase (H-PGDS) inhibitor with IC50 value of 9.4 nM and EC50 of 42 nM. HPGDS inhibitor 3 exhibits good selectivity, good pharmacokinetic parameters in mouse, rat, and dog, and no CNS toxicity. HPGDS inhibitor 3 has anti-inflammatory activity[1].

Research Areas >> Inflammation/Immunology

Signaling Pathways >> Immunology/Inflammation >> PGE synthase

IC50: 9.4 nM (H-PGDS)[1] EC50: 42 nM (H-PGDS)[1]

HPGDS inhibitor 3 (compound 1y) (1-3 mg/kg; PO and IV; single) has a lower IV clearance, similar steady state volume of distribution, longer terminal half-life, and high oral bioavailability, as well as very low brain exposures in mouse, rat and dog[1]. HPGDS inhibitor 3 (0.003-1 mg/kg; PO; single) attenuates PGD2 release to baseline levels in a dose-dependent manner[1]. HPGDS inhibitor 3 (0.003-1 mg/kg; PO; single) inhibits LPS-induced PGD2 increase in plasma and skeletal muscle in a dose-dependent manner[1]. HPGDS inhibitor 3 (1, 3, and 10 mg/kg; PO; q.d., for 16 days) significantly enhances functional recovery of injured limbs, and hastens the time to full functional recovery of injured limb muscles[1]. HPGDS inhibitor 3 (10, 30 and 100 mg/kg; PO; once daily, for 7 days) exhibits well tolerated at 30 mg/kg/day in rat but not tolerated at 100 mg/kg/day[1]. HPGDS inhibitor 3 (10, 30, and 75 mg/kg; PO; once daily, for 4 days) shows well tolerated at 30 mg/kg/day in dogs but not tolerated at 75 mg/kg/day[1]. Pharmacokinetic Parameters of HPGDS inhibitor 3 in mice, rats and dogs[1]. Mouse IV, 1 mg/kg PO, 3 mg/kg Rat IV, 0.4 mg/kg PO, 2.4 mg/kg Dog IV, 0.5 mg/kg PO, 1 mg/kg T1/2 (h) 2.9 5.1 6.2 CL (mL/min/kg) 9.0 4.5 1.9 Vss (L/kg) 1.6 1.6 1.0 F (%) 71 100 92 Brain:blood ratio 0.06

[1]. Cadilla R, Deaton DN, Do Y, et al. The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure. Bioorg Med Chem. 2020;28(23):115791.