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, 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.
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- CAS No.: 2255311-93-2
- Formula: C21H27N3O2
- Molecular Weight:353.46
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
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Biological Activity
Description
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].
IC50 & Target
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| Mast cell | EC50 |
3.4 nM
Compound: 1y
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Anti-inflammatory activity against mast cell degranulation inflammatory C57BL/6J mouse model assessed as blood EC50 required for reduction in compound 48/80-induced PGD2 release into peritoneal lavage fluid administered orally with compound and 1 hr later
Anti-inflammatory activity against mast cell degranulation inflammatory C57BL/6J mouse model assessed as blood EC50 required for reduction in compound 48/80-induced PGD2 release into peritoneal lavage fluid administered orally with compound and 1 hr later
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[PMID: 33059303] |
| Mast cell | ED50 |
0.009 mg/kg
Compound: 1y
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Anti-inflammatory activity against mast cell degranulation inflammatory C57BL/6J mouse model assessed as reduction in compound 48/80-induced PGD2 release into peritoneal lavage fluid administered orally with compound and 1 hr later treated with compound 4
Anti-inflammatory activity against mast cell degranulation inflammatory C57BL/6J mouse model assessed as reduction in compound 48/80-induced PGD2 release into peritoneal lavage fluid administered orally with compound and 1 hr later treated with compound 4
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[PMID: 33059303] |
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].
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 |
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| 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 |
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Male C57BL/6J mice (murine mast cell degranulation model of inflammation)[1]
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Dosage:0.003, 0.01, 0.03, 0.1, 0.3 and 1.0 mg/kg
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Administration:PO; single (anesthetized 1 hour later, intraperitoneally injected with 0.2 mL PBS or 48/80 (0.75 mg/mL))
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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.
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Animal Model:Male C57BL6/N mice (12 weeks, n=6)[1]
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Dosage:0.003, 0.01, 0.03, 0.1, 0.3 and 1.0 mg/kg
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Administration:PO; single (intraperitoneally injection of PBS or 20 ng/kg LPS 1 hour later)
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Result:Inhibited LPS-induced PGD2 increase in plasma and skeletal muscle in a dose-dependent manner.
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Animal Model:Male C57Bl/6 mice (10-12 weeks, n=7-8; chronic eccentric contraction-induced muscle injury models)[1]
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Dosage:1, 3, and 10 mg/kg
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Administration:PO; q.d., for 16 days
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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..
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Animal Model:Mdx mouse (6-8 mouths, duchenne muscular dystrophy model)[1]
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Dosage:0.1, 0.3, 1, 3, and 10 mg/kg
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Administration:PO; q.d., for 43 days
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Result:Significantly improved functional recovery (~90% to 100% restoration), following eccentric contraction-induced muscle injury in mdx mice.
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Animal Model:Male Wistar Han rat and dog[1]
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Dosage:10, 30 and 100 mg/kg for rat; 10, 30, and 75 mg/kg for dog
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Administration:PO; once daily; for 7 days (rat) or for 4 days (dog)
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Result:In rat, the AUC values at 10, 30, and 100 mg/kg/day were 120, 410, and 820 µg•hr/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.
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Animal Model:Mice, rats, dongs[1]
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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
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Administration:IV and PO; single (Pharmacokinetics Analysis)
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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.
Chemical Information
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CAS No. 2255311-93-2
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Molecular Weight 353.46
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Formula C21H27N3O2
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SMILES
CC(O)([C@H]1CC[C@@H](CC1)NC(C2=CC3=CC=C(N=C3N=C2)C4CC4)=O)C
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
Select Batch:
Purity:
99.98%
Assay:
99.98%
ee.:
99.98%
References
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