1,8-Naphthyridine-3-carboxamide, 7-cyclopropyl-N-[trans-4-(1-hydroxy-1-methylethyl)cyclohexyl]- manufacturers
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| | 1,8-Naphthyridine-3-carboxamide, 7-cyclopropyl-N-[trans-4-(1-hydroxy-1-methylethyl)cyclohexyl]- Basic information |
| | 1,8-Naphthyridine-3-carboxamide, 7-cyclopropyl-N-[trans-4-(1-hydroxy-1-methylethyl)cyclohexyl]- Chemical Properties |
| Boiling point | 604.7±50.0 °C(Predicted) | | density | 1.22±0.1 g/cm3(Predicted) | | pka | 12.92±0.40(Predicted) |
| | 1,8-Naphthyridine-3-carboxamide, 7-cyclopropyl-N-[trans-4-(1-hydroxy-1-methylethyl)cyclohexyl]- Usage And Synthesis |
| Uses | 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, respectively. 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]. | | in vivo | 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; also inhibits LPS-induced PGD2 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 | | 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 | | |
| 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 PGD2 release to baseline levels in a dose-dependent manner with an ED50 of 0.009 mg/kg (blood EC50 = 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 μghr/mL, respectively; respective Cmax 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. |
| | References | [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. DOI:10.1016/j.bmc.2020.115791 |
| | 1,8-Naphthyridine-3-carboxamide, 7-cyclopropyl-N-[trans-4-(1-hydroxy-1-methylethyl)cyclohexyl]- Preparation Products And Raw materials |
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