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Purity: ≥98%
PD146176 (alfo known as NSC168807) is a novel and potent 15-Lipoxygenase (15-LO) inhibitor which inhibits rabbit reticulocyte 15-LO with a Ki of 197 nM. PD146176 (NSC168807) has a dramatic effect in reducing atherogenesis.
| Targets |
PD146176 is a specific inhibitor of rabbit reticulocyte 15-lipoxygenase (15-LO) with a Ki of 197 nM. It exhibits minimal inhibitory effects on 5-LO (0% at 10 µM), 12-LO (0% at 10 µM), ovine cyclo-oxygenase I (26% at 10 µM), and human recombinant cyclo-oxygenase II (16% at 10 µM).
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| ln Vitro |
PD146176, with an IC50 of 0.81 μM, suppresses the formation of 13-HODE in intact IC21 cells transfected with human 15-LO [2].
PD146176 inhibited rabbit reticulocyte 15-LO through a mixed noncompetitive mode with a Ki of 197 nM.[1] At concentrations achievable in vivo (~45 ng/mL), PD146176 provided no significant protection of human LDL against ABAP-induced lipid peroxidation. A significant increase in lag time for LDL oxidation was observed only at a concentration (1000 ng/mL) considerably above the plasma concentration achieved in vivo.[1] PD146176 failed to reduce 13-HPODE (the product of linoleate incubated with 15-LO) to the corresponding hydroxy fatty acid and showed no activity in a linoleate-containing SDS micelle assay designed to detect antioxidant potential. |
| ln Vivo |
By inducing autophagy in the aged triple renal pelvis, PD146176 (80 mg/kg; chewable; 12 weeks) ameliorates cognitive impairment, cerebral amyloidosis, and tau pathology [3].
Administration of PD146176 (175 mg/kg, b.i.d., in diet) for 12 weeks to cholesterol-fed rabbits dramatically suppressed atherogenesis. In the aortic arch, lesion coverage diminished from 15 ± 4% to 0% (P < 0.02), and esterified cholesterol content was reduced from 2.1 ± 0.7 to 0 µg/mg (P < 0.02).[1] Immunostainable lipid-laden macrophages present in the aortic intima of control animals were totally absent in the drug-treated group.[1] The drug did not significantly alter plasma total cholesterol concentrations or the distribution of VLDL, LDL, or HDL cholesterol, but did increase the concentration of the lipoprotein fraction designated as VLDL remnants.[1] LDL isolated from PD146176-treated rabbits was as susceptible to ex vivo oxidation by copper or ABAP as LDL from control animals, indicating no significant in vivo antioxidant effect at the achieved plasma concentrations. |
| Enzyme Assay |
15-LO was isolated from reticulocytes harvested from phenylhydrazine-treated rabbits. The enzyme (820 pmol) was incubated for 20 minutes at 4°C in Dulbecco's phosphate-buffered saline (pH 7.4) without calcium, containing HEPES (10 mM), ovalbumin (1 mg/mL), glycerol (10% v/v), MgCl₂ (5 mM), sodium cholate (4.4 mM), DMSO (5% v/v), and the required concentration of PD146176 for 15 minutes. The reaction was initiated by adding 13-hydroperoxyoctadecadienoate (13-HPODE) and [¹⁴C]-linoleic acid (1.5 to 48 µM) at 4°C. Aliquots of the reaction mixture were withdrawn at selected intervals and quenched by adding methanol and triphenylphosphine (100 µg). The production of [¹⁴C]-13-HODE in the presence of increasing drug concentrations was monitored by reverse-phase HPLC. The concentration causing 50% inhibition (IC50) was determined by fitting the data to a two-parameter equation. Reaction velocities were calculated by linear regression of product values versus reaction time, and data were fitted to classical rapid equilibrium models using hyperbolic weighting.
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| Animal Protocol |
Animal/Disease Models: Triple transgenic (3xTg) mice [3]
Doses: 80mg/kg Route of Administration: chewing; 12-week Experimental Results: Significant reduction in beta-amyloid levels and deposition, diminished tau neuropathology, increased synaptic integrity, Autophagy activation. Specific pathogen-free New Zealand White rabbits (≈2.5 kg) were fed a high-fat diet containing 0.25% (wt/wt) cholesterol, 3% peanut oil, and 3% coconut oil for 12 weeks. The drug-treated group received PD146176 mixed into their food at a total dose of 350 mg/kg body weight per day, administered as 175 mg/kg twice daily (b.i.d.) via automated feeders that provided 40g of food at ≈12-hour intervals. Control animals received the same diet without the drug. Body weights were measured weekly. Blood samples were collected at intervals for hematocrit and plasma lipid analysis. Animals were euthanized after 12 weeks by an overdose of sodium pentobarbitone (150 mg/kg) and exsanguination. |
| ADME/Pharmacokinetics |
During the 12-week study, plasma samples were analyzed by high-performance liquid chromatography (HPLC) with PD146176 administered twice daily via diet at a dose of 175 mg/kg. The results showed that the plasma drug concentration remained close to the estimated Ki value (assuming a molecular weight of 197 nM ≈ 45 ng/mL).
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| Toxicity/Toxicokinetics |
During the 12-week study period, PD146176 was well tolerated in rabbits, and no significant clinical toxicity was observed. The weight gain was comparable between the control group (2.88 ± 0.36 kg) and the drug treatment group (2.84 ± 0.21 kg).
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| References |
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| Additional Infomation |
PD-146176 is an organic heterotetracyclic compound with the structure 1H-indole and a 2H-1-benzothiophene group fused at the 2-3 ortho positions. It is a 15-lipoxygenase inhibitor that limits the progression of atherosclerotic lesions in rabbits. It has the effects of ferroptosis inhibitor, EC 1.13.11.33 (arachidonic acid 15-lipoxygenase) inhibitor and anti-atherosclerotic agent. It is an organic heterotetracyclic compound, an organic sulfur heterocyclic compound and an organic nitrogen heterocyclic compound. PD146176 (6,11-dihydro-5-thia-11-azabenzo[a]fluorene) is a novel compound synthesized based on the prototype structure and has been identified as a highly selective 15-lipoxygenase inhibitor with no significant non-specific antioxidant properties. [1] This study provides evidence to support the role of 15-lipoxygenase in the pathogenesis of atherosclerosis.
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| Molecular Formula |
C15H11NS
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| Molecular Weight |
237.319542169571
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| Exact Mass |
237.061
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| CAS # |
4079-26-9
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| PubChem CID |
297589
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
485.4±24.0 °C at 760 mmHg
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| Flash Point |
247.4±22.9 °C
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| Vapour Pressure |
0.0±1.2 mmHg at 25°C
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| Index of Refraction |
1.774
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| LogP |
4.38
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
1
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
17
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| Complexity |
293
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
ZGOOPZVQMLHPFM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H11NS/c1-3-7-13-10(5-1)12-9-17-14-8-4-2-6-11(14)15(12)16-13/h1-8,16H,9H2
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| Chemical Name |
6,11-dihydro-[1]benzothiopyrano[4,3-b]indole
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| Synonyms |
PD 146176; PD-146176; PD146176; NSC 168807; NSC-168807; NSC168807.
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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 |
| 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) |
DMSO : ~25 mg/mL (~105.34 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (10.53 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (10.53 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (10.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.2137 mL | 21.0686 mL | 42.1372 mL | |
| 5 mM | 0.8427 mL | 4.2137 mL | 8.4274 mL | |
| 10 mM | 0.4214 mL | 2.1069 mL | 4.2137 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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