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| 5mg |
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| 10mg |
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| 25mg |
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ACHP hydrochloride (also known as IKK-2 Inhibitor VIII), the hydrochloride salt of ACHP, is a novel, highly potent and selective IKK-β inhibitor with IC50 of 8.5 nM.
| Targets |
IKK-β (IC50 = 8.5 nM); IKK-α (IC50 = 250 nM)
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|---|---|
| ln Vitro |
In A549 cells, ACHP hydrochloride (Compound 4j) exhibits strong IKK- inhibitory (IC50: 8.5 nM) and cellular activities (IC50=40 nM). IKK- is moderately inhibited by ACHP with an IC50 of 250 nM, but other kinases, including IKK3, Syk, and MKK4 (IC50>20,000 nM), are well-selectively inhibited. Additionally, ACHP exhibits strong activity in a variety of cellular assays. In TNFα-activated HEK293 cells and PMA/calcium ionophore-activated Jurkat T cells, ACHP inhibits NF-κB-dependent reporter gene activation. Even at concentrations greater than 10 μM, ACHP cannot prevent PMA-induced AP-1 activation in MRC-5 cells or PMA/calcium ionophore-induced NF-κB dependent reporter gene transcription in Jurkat cells. Through the inhibition of IKK-β in living cells, ACHP specifically disrupts the NF-κB signaling cascade[1]. In a dose-dependent manner, ACHP slows the growth of these cells. Tax-active cell lines are more sensitive to ACHP than Tax-inactive cell lines or Jurkat (IC50 values in Tax-active cell lines, Tax-inactive cell lines, or Jurkat are 3.1±1.3 μM, 10.7±1.7 μM and 23.6 μM, respectively), which may indicate that Tax-active cells are more dependent on NF-κB for growth than Tax-inactive cells are[2].
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| ln Vivo |
In mice and rats, ACHP (Compound 4j) is orally bioavailable and exhibits significant in vivo anti-inflammatory activity (arachidonic acid-induced mouse ear edema model). The oral bioavailability of ACHP in mice (BA: 16%) and rats (BA: 60%) shows that it has a good Caco-2 permeability (Papp 62.3×10-7 cm/s) and a reasonable aqueous solubility (0.12 mg/mL in pH 7.4 isotonic buffer). Because of its low clearance (0.33 L/h/kg), ACHP has a favorable bioavailability in rats. In a dose-dependent manner, oral efficacy of ACHP at 1 mg/kg is shown in a model of acute inflammation[1].
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| Cell Assay |
In this study, human ATL cell lines derived from ATL patients, ATL-102, ED-40515(−), and TL-Om1 cells, HTLV-1-negative T-cell leukemia cell line Jurkat, HTLV-1-infected T-cell lines, ATL-35T, 81-66/45, MJ, and MT-2 cells, and human ATL cell lines derived from ATL patients are all used. In triplicates, 1.5×104 cells are cultured in 96-well plates at 37°C. The MTT assay is used to determine the growth-inhibitory effect of ACHP (0.01, 0.1, 1, 5, 10, 50, and 100 M). A multiplate reader is used to measure the optical densities (OD) at 570 and 630 nm. Calculations of cell viability (%) are made[2].
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| Animal Protocol |
Mice: In vivo arachidonic acid-induced mouse ear edema: 500 μg/ear topical application of arachidonic acid causes ear edema. 60 minutes prior to the application of arachidonic acid, the vehicle (10% cremophor in saline) and ACHP (0.3, 1 and 3 mg/kg, p.o.) are administered. After applying the arachidonic acid, the ear thickness is measured at 0, 1, 3, and 6 hours.
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| References |
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| Molecular Formula |
C21H24N4O2.HCL
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|---|---|
| Molecular Weight |
400.9018
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| Exact Mass |
400.167
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| Elemental Analysis |
C, 62.92; H, 6.29; Cl, 8.84; N, 13.98; O, 7.98
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| CAS # |
406209-26-5
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| Related CAS # |
406208-42-2
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| PubChem CID |
136216943
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| Appearance |
Off-white to yellow solid
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| LogP |
4.224
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
28
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| Complexity |
540
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N#CC1=C(C=C(N=C1N)C2=C(C=CC=C2OCC3CC3)O)C4CCNCC4.[H]Cl
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| InChi Key |
QVYAMWAKDKEKMM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H24N4O2.ClH/c22-11-16-15(14-6-8-24-9-7-14)10-17(25-21(16)23)20-18(26)2-1-3-19(20)27-12-13-4-5-13;/h1-3,10,13-14,24,26H,4-9,12H2,(H2,23,25);1H
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| Chemical Name |
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-ylpyridine-3-carbonitrile;hydrochloride
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| Synonyms |
ACHP Hydrochloride; IKK-2 Inhibitor VIII
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 : ~100 mg/mL (~249.44 mM)
H2O : < 0.1 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 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 (6.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4944 mL | 12.4719 mL | 24.9439 mL | |
| 5 mM | 0.4989 mL | 2.4944 mL | 4.9888 mL | |
| 10 mM | 0.2494 mL | 1.2472 mL | 2.4944 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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