406209-26-5
基本信息
IKK-2 inhibitor VIII
ACHP (Hydrochloride )
Bayer IKK-beta inhibitor
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-
2-Amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridinecarbonitrile hydrochloride
2-amino-6-[2-(cyclopropylmethoxy)-6-oxocyclohexa-2,4-dien-1-ylidene]-4-piperidin-4-yl-1H-pyridine-3-carbonitrile
3-Pyridinecarbonitrile, 2-aMino-6-[2-(cyclopropylMethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-, hydrochloride (1:1)
(6E)-2-amino-6-[2-(cyclopropylmethoxy)-6-oxocyclohexa-2,4-dien-1-ylidene]-4-piperidin-4-yl-1H-pyridine-3-carbonitrile
(6Z)-2-amino-6-[2-(cyclopropylmethoxy)-6-oxocyclohexa-2,4-dien-1-ylidene]-4-piperidin-4-yl-1H-pyridine-3-carbonitrile
物理化學(xué)性質(zhì)
常見問題列表
IKK-β 8.5 nM (IC 50 ) |
IKK-α 250 nM (IC 50 ) |
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.