2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(4-哌啶基)-3-吡啶甲腈盐酸盐

ACHP Hydrochloride (Compound 4j) exhibits potent IKK-β inhibitory (IC ₅₀ : 8.5 nM) and cellular activities (IC ₅₀ =40 nM, in A549 cells). ACHP moderately inhibits IKK-α with an IC ₅₀ of 250 nM but exhibits good selectivity towards other kinases, such as IKK3, Syk and MKK4 (IC ₅₀ >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. 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 (IC ₅₀ 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.

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.