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1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one

ChemBase编号:73181
分子式:C25H24N6O2
平均质量:440.49706
单一同位素质量:440.19607404
SMILES和InChIs

SMILES:
c1nc(c2c(n1)n(nc2c1ccc(cc1)Oc1ccccc1)C1CN(CCC1)C(=O)C=C)N
Canonical SMILES:
C=CC(=O)N1CCCC(C1)n1nc(c2c1ncnc2N)c1ccc(cc1)Oc1ccccc1
InChI:
InChI=1S/C25H24N6O2/c1-2-21(32)30-14-6-7-18(15-30)31-25-22(24(26)27-16-28-25)23(29-31)17-10-12-20(13-11-17)33-19-8-4-3-5-9-19/h2-5,8-13,16,18H,1,6-7,14-15H2,(H2,26,27,28)
InChIKey:
XYFPWWZEPKGCCK-UHFFFAOYSA-N

引用这个纪录

CBID:73181 http://www.chembase.cn/molecule-73181.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one
IUPAC传统名
1-{3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one
别名
PCI-32765
CAS号
936563-96-1
PubChem SID
162038101
PubChem CID
16126651

数据来源

数据来源

所有数据来源 商品来源 非商品来源
数据来源 数据ID 价格
Selleck Chemicals
S2680 external link 加入购物车 请登录
数据来源 数据ID
PubChem 16126651 external link

理论计算性质

理论计算性质

JChem
Acid pKa 19.696075  质子受体
质子供体 LogD (pH = 5.5) 2.5686305 
LogD (pH = 7.4) 3.5700207  Log P 3.6302264 
摩尔折射率 138.0741 cm3 极化性 49.58703 Å3
极化表面积 99.16 Å2 可自由旋转的化学键
里宾斯基五规则 true 

分子性质

分子性质

安全信息 产品相关信息 生物活性(PubChem)
保存条件
-20°C expand 查看数据来源
成盐信息
Free Base expand 查看数据来源

详细说明

详细说明

Selleck Chemicals Selleck Chemicals
Selleck Chemicals -  S2680 external link
Research Area
Description Mantle cell lymphoma ,Chronic lymphocytic leukaemia
Biological Activity
Description PCI-32765 (Ibrutinib) is a potent and highly selective Btk inhibitor with IC50 of 0.5 nM.
Targets

Btk

IC50

0.5 nM [1]

In Vitro PCI-32765 shows the potent and irreversible inhibitory effect and selectivity for Btk enzymatic activity. In BCR pathway-activated DOHH2 cell line, PCI-32765 inhibits autophosphorylation of Btk, phosphorylation of Btk's physiological substrate PLCγ, and phosphorylation of further downstream kinase, ERK with IC50 of 11 nM, 29 nM and 13 nM, respectively. [1] PCI-32765 exhibits a significant dose-dependent and time-dependent induction of cytotoxicity in chronic lymphocytic leukemia (CLL) cells. In addition, PCI-32765 induces cell death depending on caspase pathway activation and antagonizes the ability of CLL cells to proliferate after TLR signaling. [2] A recent study shows that PCI-32765 inhibits BCR-activated primary B cell proliferation with IC50 of 8 nM and results in inhibition of TNFα, IL-1β and IL-6 production in primary monocytes with IC50 of 2.6 nM, 0.5 nM and 3.9 nM, respectively. [3]
In Vivo In a collagen-induced arthritis model, PCI-32765 significantly reduces clinical arthritis scores reflecting paw swelling and joint inflammation by inhibiting B-cell activation. In a MRL-Fas(lpr) lupus model, PCI-32765 reduces renal disease and autoantibody production. [1] In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 (25 mg/kg/day) causes a transient early lymphocytosis, and delays CLL disease progression. [4]
Clinical Trials PCI-32765 is currently in Phase II clinical trials in patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Combination of PCI-32765 and Rituximab is currently in Phase II clinical trials in patients with High-Risk Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL).
Features
Combination Therapy
Description The use of PCI-32765 in combination with Bendamustine and Rituximab is currently in Phase III clinical trials in patients with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma.
Protocol
Kinase Assay [1]
Kinase Assays In vitro kinase IC50 values are measured using 33P filtration binding assay after 1 hour incubation of kinase, 33P-ATP, PCI-32765, and substrate [0.2 mg/mL poly(EY)(4:1]. Assays are performed at Reaction Biology.
Cell Assay [2]
Cell Lines Chronic lymphocytic leukemia (CLL) cells
Concentrations 0.01-100 μM
Incubation Time 48 hours
Methods

MTT (3'[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assays are performed to determine cytotoxicity. Briefly, cells (CLL B cells or healthy volunteer T cells or NK cells) are incubated for 48 hours with different concentrations of PCI-32765, or vehicle control. MTT reagent is then added, and plates are incubated for an additional 20 hours before washing with protamine sulfate in phosphate-buffered saline. Dimethyl sulfoxide is added, and absorbance is measured by spectrophotometry at 540 nm in a Labsystems plate reader. Cell viability is also measured at various time points with the use of annexin/PI flow cytometry. Data are analyzed with Expo-ADC32 software package. Results are expressed as the percentage of total positive cells over untreated control. Experiments examining caspase-dependent apoptosis includes the addition of 100μM Z-VAD.

Animal Study [1]
Animal Models MRL-Fas(lpr) lupus model and collagen-induced arthritis model.
Formulation PCI-32765 is dissolved in DMSO.
Doses ≤50 mg/kg
Administration Administered via p.o.
References
[1] Honigberg LA, et al. Proc Natl Acad Sci U S A. 2010, 107(29), 13075-13080.
[2] Herman SE, et al. Blood. 2011, 117(23), 6287-6296.
[3] Chang BY, et al. Arthritis Res Ther. 2011, 13(4), R115.
[4] Ponader S, et al. Blood. 2012, 119(5), 1182-1189.

参考文献

参考文献

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专利

专利

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