| 體內(nèi)活性 | 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 PGD 2 release to baseline levels in a dose-dependent manner; also inhibits LPS-induced PGD 2 increase in plasma and skeletal muscle in a dose-dependent manner [1]. HPGDS inhibitor 3 (0.003-1 mg/kg; PO; single) [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 or 4 days) exhibits well tolerated at 30 mg/kg/day in rat but not tolerated at 100 mg/kg/day; 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 T 1/2 (h) 2.9 5.1 6.2 CL (mL/min/kg) 9.0 4.5 1.9 V ss (L/kg) 1.6 1.6 1.0 F (%) 71 100 92 Brain:blood ratio 0.06 Animal Model: Male C57BL/6J mice (murine mast cell degranulation model of inflammation) [1] Dosage: 0.003, 0.01, 0.03, 0.1, 0.3 and 1.0 mg/kg Administration: PO; single (anesthetized 1 hour later, intraperitoneally injected with 0.2 mL PBS or 48/80 (0.75 mg/mL)) Result: Attenuated PGD 2 release to baseline levels in a dose-dependent manner with an ED 50 of 0.009 mg/kg (blood EC 50 = 3.4 nM) in this acute inflammation model. Animal Model: Male C57BL6/N mice (12 weeks, n=6) [1] Dosage: 0.003, 0.01, 0.03, 0.1, 0.3 and 1.0 mg/kg Administration: PO; single (intraperitoneally injection of PBS or 20 ng/kg LPS 1 hour later) Result: Inhibited LPS-induced PGD2 increase in plasma and skeletal muscle in a dose-dependent manner. Animal Model: Male C57Bl/6 mice (10-12 weeks, n=7-8; chronic eccentric contraction-induced muscle injury models) [1] Dosage: 1, 3, and 10 mg/kg Administration: PO; q.d., for 16 days Result: Significantly enhanced functional recovery of injured limbs, and significantly hastened the time to full functional recovery of injured limb muscles, with maximal efficacy observed at ≥ 10 mg/kg q.d.. Animal Model: Mdx mouse (6-8 mouths, duchenne muscular dystrophy model) [1] Dosage: 0.1, 0.3, 1, 3, and 10 mg/kg Administration: PO; q.d., for 43 days Result: Significantly improved functional recovery (~90% to 100% restoration), following eccentric contraction-induced muscle injury in mdx mice. Animal Model: Male Wistar Han rat and dog [1] Dosage: 10, 30 and 100 mg/kg for rat; 10, 30, and 75 mg/kg for dog Administration: PO; once daily; for 7 days (rat) or for 4 days (dog) Result: In rat, the AUC values at 10, 30, and 100 mg/kg/day were 120, 410, and 820 μg hr/mL, respectively; respective C max values were 8.7, 24, and 57 μg/mL. In dog, it showed well tolerated at dose levels up to 30 mg/kg/day with no abnormal microscopic findings; but exhibited discoloration in the small intestine and esophagus (female) at 75 mg/kg/day. Animal Model: Mice, rats, dongs [1] Dosage: 1 mg/kg IV and 3 mg/kg p.o in mice, 0.4 mg/kg IV and 2.4 mg/kg PO in rat, 0.5 mg/kg IV and 1 mg/kg PO in dog Administration: IV and PO; single (Pharmacokinetics Analysis) Result: Had 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. |