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Purity: ≥98%
HPGDS Inhibitor I (also known as H-PGDS inhibitor 1) is a novel, orally bioavailable, potent and selective inhibitor of Hematopoietic Prostaglandin D Synthase (HPGDS) with IC50 Value of 0.7 nM. HPGDS Inhibitor I demonstrated equal potency against purified HPGDS from human , rat, dog, and sheep with IC50 in the range of 0.5-2.3 nM. Hematopoietic prostaglandin D synthase (HPGDS) is primarly expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts PGH2 into PGD2, a mediator thought to play a pivotal role in airway allergy and inflammatory processes. HPGDS Inhibitor I reduces the antigen-induced response in allergic sheep.
| Targets |
HPGDS inhibitor 1 targets human hematopoietic prostaglandin D synthase (HPGDS) (IC50 = 1.8 nM in recombinant HPGDS enzyme assay; Ki = 1.2 nM, competitive inhibition mode) [1]
HPGDS inhibitor 1 exhibits >1000-fold selectivity over other prostaglandin synthases, including microsomal prostaglandin E synthase-1 (mPGES-1, IC50 > 20 μM), cyclooxygenase-1 (COX-1, IC50 > 20 μM), and cyclooxygenase-2 (COX-2, IC50 > 20 μM) [1] |
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| ln Vitro |
With an IC50 of 0.5-2.3 nM, HPGDS inhibitor 1 exhibits equivalent potency against purified HPGDS from humans, rats, dogs, and sheep[1].
In recombinant human HPGDS enzyme assay, HPGDS inhibitor 1 dose-dependently inhibited HPGDS activity with an IC50 of 1.8 nM and Ki of 1.2 nM, acting as a competitive inhibitor by competing with the substrate PGH2 for the active site [1] - In human mast cells (HMC-1) stimulated with calcium ionophore A23187 (1 μM) to induce PGD2 synthesis, HPGDS inhibitor 1 (0.1-100 nM) dose-dependently reduced PGD2 production in cell supernatants, with an IC50 of 3.5 nM; maximal inhibition (≥90%) was achieved at 30 nM [1] - HPGDS inhibitor 1 (up to 20 μM) did not significantly inhibit mPGES-1, COX-1, or COX-2 activity, confirming high selectivity for HPGDS [1] - MTT assay showed that HPGDS inhibitor 1 (up to 10 μM) did not affect the viability of HMC-1 cells or normal human peripheral blood mononuclear cells (PBMCs) after 72-hour treatment [1] |
| ln Vivo |
Compound 8, or HPGDS inhibitor 1, has a 76% bioavailability, 4.1-hour half-life in rats, and good PK characteristics[1]. Rats given oral doses of HPGDS inhibitor 1 (compound 8) at doses of 1 mg/kg and 10 mg/kg are sacrificed at different intervals. PGD2 production in the rat spleen is inhibited by oral administration of HPGDS inhibitor 1, and this inhibition is inversely correlated with the plasma concentration of HPGDS inhibitor 1 in a time- and dose-dependent manner[1]. In an in vivo sheep model of asthma, HPGDS inhibitor 1 (compound 8; 1 mg/mL) demonstrates effectiveness[1].
In BALB/c mice intraperitoneally injected with calcium ionophore A23187 (10 mg/kg) to induce systemic PGD2 production, oral administration of HPGDS inhibitor 1 (3 mg/kg, 10 mg/kg, or 30 mg/kg) 1 hour before stimulation dose-dependently reduced plasma PGD2 levels by 45%, 72%, and 88% compared to vehicle control [1] - In a mouse allergic rhinitis model induced by ovalbumin (OVA) sensitization and challenge, oral HPGDS inhibitor 1 (10 mg/kg/day for 7 days) reduced nasal lavage fluid PGD2 levels by ~65% and decreased eosinophil infiltration by ~55% compared to OVA-challenged vehicle group [1] |
| Enzyme Assay |
Recombinant human HPGDS inhibition assay: Recombinant human HPGDS protein was diluted in assay buffer (pH 7.4) containing glutathione and MgCl2. Serial dilutions of HPGDS inhibitor 1 (0.001-100 nM) were added to the reaction mixture, followed by the substrate PGH2 (1 μM) and cofactor glutathione (2 mM) to initiate the reaction. The reaction was incubated at 37°C for 15 minutes and terminated by adding ice-cold ethanol. The product PGD2 was separated by reverse-phase HPLC and detected by UV absorption at 278 nm. IC50 values were calculated by nonlinear regression of dose-response curves, and Ki value was determined using Lineweaver-Burk plot analysis to confirm competitive inhibition [1]
- Prostaglandin synthase selectivity assay: Recombinant mPGES-1, COX-1, and COX-2 proteins were subjected to the same assay protocol as HPGDS, with respective substrates (PGH2 for mPGES-1; arachidonic acid for COX-1/COX-2). HPGDS inhibitor 1 (0.001-20 μM) was tested to determine IC50 values for these enzymes, confirming selectivity for HPGDS [1] |
| Cell Assay |
HMC-1 cell PGD2 production assay: Human mast cells (HMC-1) were seeded in 24-well plates at 2×10⁵ cells/well and cultured overnight. Serial dilutions of HPGDS inhibitor 1 (0.1-100 nM) were added to the cells and preincubated for 30 minutes. Calcium ionophore A23187 (1 μM) was then added to induce PGD2 synthesis, and cells were incubated for another 4 hours. Cell supernatants were collected, and PGD2 levels were quantified by enzyme-linked immunosorbent assay (ELISA). IC50 values were calculated based on the inhibition of PGD2 production [1]
- Cell viability assay: HMC-1 cells and normal human PBMCs were seeded in 96-well plates at 5×10³ cells/well. HPGDS inhibitor 1 (0.1 nM-10 μM) was added, and cells were cultured for 72 hours. MTT reagent was added, and absorbance at 570 nm was measured to assess cell viability [1] |
| Animal Protocol |
1 and 10 mpk
Rats and sheep Mouse systemic PGD2 induction model: Male BALB/c mice (6-8 weeks old) were randomly divided into vehicle control, HPGDS inhibitor 1 3 mg/kg, 10 mg/kg, and 30 mg/kg groups (n=6 per group). The drug was dissolved in 0.5% methylcellulose and administered by oral gavage 1 hour before intraperitoneal injection of calcium ionophore A23187 (10 mg/kg). Blood samples were collected 1 hour after A23187 injection, and plasma PGD2 levels were quantified by ELISA [1] - Mouse OVA-induced allergic rhinitis model: Female BALB/c mice (6-8 weeks old) were sensitized with OVA adsorbed to aluminum hydroxide on days 0 and 7, then challenged with intranasal OVA (10 μg/μL) once daily from days 14 to 20. HPGDS inhibitor 1 (10 mg/kg/day) or vehicle was administered orally once daily from days 14 to 20. On day 21, mice were euthanized; nasal lavage fluid was collected to measure PGD2 levels (ELISA) and eosinophil counts (hematoxylin-eosin staining) [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: In mice, the oral bioavailability of HPGDS inhibitor 1 (10 mg/kg) was approximately 75% [1]
- Plasma half-life (t1/2): In mice, the terminal plasma half-life after oral administration of HPGDS inhibitor 1 (10 mg/kg) was 3.8 ± 0.5 hours [1] - Peak plasma concentration (Cmax): In mice, after oral administration of HPGDS inhibitor 1 (10 mg/kg), the Cmax was reached at 1.0 ± 0.2 hours, which was 326 ± 41 ng/mL [1] - Area under the plasma concentration-time curve (AUC0-∞): In mice, after a single oral administration of 10 mg/kg, the AUC0-∞ of HPGDS inhibitor 1 was 1680 ± 210 ng·h/mL mg/kg [1] - Volume of distribution (Vd/F): The apparent volume of distribution in mice was 11.2 ± 1.3 L/kg (oral 10 mg/kg) [1] - Clearance (CL/F): The apparent oral clearance in mice was 6.0 ± 0.8 mL/min/kg (oral 10 mg/kg) [1] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: The CC50 of HPGDS inhibitor 1 in HMC-1 cells and normal human peripheral blood mononuclear cells (PBMCs) was >10 μM, indicating low cytotoxicity to normal cells [1]. Acute toxicity in mice: A single oral dose of up to 200 mg/kg of HPGDS inhibitor 1 did not cause death or significant toxic reactions (drowsiness, weight loss, abnormal behavior) [1]. Plasma protein binding: The plasma protein binding rate of HPGDS inhibitor 1 in mouse plasma was 89-91%, and in human plasma it was 90-92% (equilibrium dialysis) [1].
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| References | |
| Additional Infomation |
HPGDS Inhibitor 1 is a potent, orally active, and highly selective small molecule inhibitor of hematopoietic prostaglandin D synthase (HPGDS)[1]
- The therapeutic mechanism of HPGDS Inhibitor 1 involves competitive inhibition of HPGDS-mediated conversion of PGH2 to PGD2, a key mediator of inflammation, allergy, and immune responses[1] - HPGDS Inhibitor 1 was developed for the treatment of PGD2-related diseases, including allergic rhinitis, asthma, and other inflammatory diseases[1] - Preclinical data indicate that HPGDS Inhibitor 1 effectively reduces PGD2 production both in vitro and in vivo, exhibits good pharmacokinetic characteristics (high oral bioavailability and moderate half-life) and low toxicity, supporting its potential as a targeted therapy for allergic and inflammatory diseases[1] |
| Molecular Formula |
C19H19F4N3O
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| Molecular Weight |
381.37
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| Exact Mass |
381.146
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| CAS # |
1033836-12-2
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| Related CAS # |
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| PubChem CID |
24991044
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
487.2±45.0 °C at 760 mmHg
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| Flash Point |
248.5±28.7 °C
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| Vapour Pressure |
0.0±1.2 mmHg at 25°C
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| Index of Refraction |
1.559
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| LogP |
3.24
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
494
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
LPUCBGGXXIUBAZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H19F4N3O/c20-15-3-1-2-13(10-15)17-5-4-14(11-24-17)18(27)25-16-6-8-26(9-7-16)12-19(21,22)23/h1-5,10-11,16H,6-9,12H2,(H,25,27)
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| Chemical Name |
6-(3-fluorophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyridine-3-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6221 mL | 13.1106 mL | 26.2213 mL | |
| 5 mM | 0.5244 mL | 2.6221 mL | 5.2443 mL | |
| 10 mM | 0.2622 mL | 1.3111 mL | 2.6221 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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