1. Metabolic Enzyme/Protease
  2. 5-Lipoxygenase

A-69412 

Cat. No.: HY-101945
Handling Instructions

A-69412 is a reversible, specific inhibitor of the hydrophilic 5-lipoxygenase (5-LO).

For research use only. We do not sell to patients.

A-69412 Chemical Structure

A-69412 Chemical Structure

CAS No. : 123606-23-5

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  • Biological Activity

  • Protocol

  • Technical Information

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  • References

Description

A-69412 is a reversible, specific inhibitor of the hydrophilic 5-lipoxygenase (5-LO).

IC50 & Target

IC50: 5-LO (1 μM for LTB4, 79 μM for 15 HETE, 114 μM for 12 HETE) [1].

In Vitro

A-69412 inhibits the formation of 5-HETE by the 20000×g supernatant of RBL-I cells in a dose-dependent fashion. The shift to greater potency at lower substrate concentrations is consistent with A-69412 being a competitive inhibitor of the enzyme. A-69412 also inhibits the formation of LTB4 in calcium ionophore A23187 stimulated human PMNL (IC50=8.9 μM). A-69412 is more potent in inhibiting LTB4 formation in ionophore-stimulated human whole blood. The potency of A-69412 in a number of assays using several donors consistently show activity in the low micromolar range (mean IC50=1.4 μM, range 0.5-3 μM, 9 donors), several fold more potent than its activity in the other in vitro assays[1].

In Vivo

Oral doses of A-69412 are found to inhibit leukotriene production in a number of species. For example, A-69412 is found to be a potent long-acting inhibitor of leukotriene formation in vivo in the rat (oral ED50=5 mg/kg). A-69412 is remarkably potent in the dog, giving nearly complete inhibition through 16 h after a single 5 mg/kg dose. Plasma concentrations in the dog studies are 38 μM at 0.5 h after dosing and 5 μM at 16 h. These data are consistent with the 100% inhibition seen ex vivo at 0.5 h post-dosing and the 90% inhibition seen at 16 h. As would be expected from the pharmacokinetic results, A-69412 is clearly superior to zileuton in the cynomolgus monkey. A-69412 gave >50% inhibition of ex vivo LTB4 biosynthesis in the monkey for 8 h, while zileuton is effective only in the first 2 h after oral dosing. An anaphylactic reaction in the rat peritoneal cavity of passively sensitized animals produces large amounts of sulfidopeptide leukotrienes. Given as an oral solution, A-69412 dose-dependently inhibits leukotriene production in the peritoneal cavity of the rat. In one of the experiments, blood levels of A-69412 are measured. These values range from 4 to 100 μM with doses ranging from 2 to 50 mg/kg. A-69412 also significantly inhibits the reaction if dosed (10 mg/kg) at times up to 8 h before challenge. Plasma concentrations of A-69412 are measured in the time course studies and are found to range from 44 μM at 0.5 h to 10 μM at 8 h after dosing[1].

Solvent & Solubility
In Vitro: 

10 mM in H2O

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 5.8765 mL 29.3824 mL 58.7648 mL
5 mM 1.1753 mL 5.8765 mL 11.7530 mL
10 mM 0.5876 mL 2.9382 mL 5.8765 mL
*Please refer to the solubility information to select the appropriate solvent.
References
Animal Administration
[1]

Dogs, Rats and Monkeys[1]
A-69412 is suspended in 0.2% methylcellulose with a Potter-Elvehjem homogenizer equipped with a Teflon-coated pestle and administered orally (20 mg/kg) to beagle dogs, cynomolgus monkeys and male Sprague-Dawley rats. Zileuton is used for comparison. All animals are fasted overnight before dosing but allowed water ad libitum. Heparinized blood samples are obtained before and at various times after compound administration in the dog and monkey studies. Groups of rats are dosed with vehicle or A-69412 and 1 h and 15 min later, the animals are sacrificed and blood collected by cardiac puncture into heparinized syringes. Aliquots of blood from all the three species are incubated at 37°C with 50 μM calcium ionophore, A23187. After 30min, the blood is placed in an ice bath and analyzed for LTB4[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

170.17

Formula

C₇H₁₀N₂O₃

CAS No.

123606-23-5

SMILES

O=C(N)N(C(C1=COC=C1)C)O

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Shipping

Room temperature in continental US; may vary elsewhere

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Product Name:
A-69412
Cat. No.:
HY-101945
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A-69412

Cat. No.: HY-101945