ACHP Hydrochloride  (Synonyms: IKK-2 Inhibitor VIII)

ACHP Hydrochloride (IKK-2 Inhibitor VIII) is a highly potent and selective IKK-β inhibitor with an IC₅₀ of 8.5 nM.

ACHP Hydrochloride (Compound 4j) exhibits potent IKK-β inhibitory (IC₅₀: 8.5 nM) and cellular activities (IC₅₀=40 nM, in A549 cells). ACHP moderately inhibits IKK-α with an IC₅₀ of 250 nM but exhibits good selectivity towards other kinases, such as IKK3, Syk and MKK4 (IC₅₀>20,000 nM). Moreover, ACHP demonstrates quite potent activity in various cellular assays. ACHP inhibits NF-κB-dependent reporter gene activation in TNFα-activated HEK293 cells and PMA/calcium ionophore-activated Jurkat T cells. ACHP fails to inhibit PMA-induced AP-1 activation in MRC-5 cells and PMA/calcium ionophore induced NF-κB dependent reporter gene transcription in Jurkat cells even at concentrations exceeding 10 μM. ACHP selectively interferes with the NF-κB signaling cascade by inhibition of IKK-β in living cells^[1]. ACHP inhibits the growth of these cells in a dose-dependent manner. Tax-active cell lines are more susceptible to ACHP than Tax-inactive cell lines and 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), suggesting that the growth of Tax-active cells depends on NF-κB more than Tax-inactive cells^[2].

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

ACHP (Compound 4j) is orally bioavailable in mice and rats and demonstrates significant in vivo activity in anti-inflammatory models (arachidonic acid-induced mouse ear edema model). ACHP has reasonable aqueous solubility (0.12 mg/mL in pH 7.4 isotonic buffer) and excellent Caco-2 permeability (P_app 62.3×10^-7 cm/s), and demonstrates orally bioavailability in mice (BA: 16%) and rats (BA: 60%). The favourable bioavailability of ACHP in rats is likely due to its low clearance (0.33 L/h/kg). In an acute inflammation model, ACHP exhibits oral efficacy at 1 mg/kg in a dose-dependent manner^[1].

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

400.90

Solid

C₂₁H₂₅ClN₄O₂

406209-26-5

N#CC1=C(C=C(N=C1N)C2=C(C=CC=C2OCC3CC3)O)C4CCNCC4.[H]Cl

Room temperature in continental US; may vary elsewhere.

4°C, stored under nitrogen

*In solvent : -80°C, 6 months; -20°C, 1 month (stored under nitrogen)

• [1]. Murata T, et al. Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents. Bioorg Med Chem Lett. 2004 Aug 2;14(15):4019-22.  [Content Brief]

  [2]. Sanda T, et al. Induction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor. Leukemia. 2006 Apr;20(4):590-8.  [Content Brief]