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741713-40-6 分子结构
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5-(2,3-difluoro-6-methoxybenzoyl)-2-N-(1-methanesulfonylpiperidin-4-yl)pyrimidine-2,4-diamine

ChemBase编号:5722
分子式:C18H21F2N5O4S
平均质量:441.4522464
单一同位素质量:441.12823162
SMILES和InChIs

SMILES:
N1(CCC(CC1)Nc1ncc(c(n1)N)C(=O)c1c(c(ccc1OC)F)F)S(=O)(=O)C
Canonical SMILES:
COc1ccc(c(c1C(=O)c1cnc(nc1N)NC1CCN(CC1)S(=O)(=O)C)F)F
InChI:
InChI=1S/C18H21F2N5O4S/c1-29-13-4-3-12(19)15(20)14(13)16(26)11-9-22-18(24-17(11)21)23-10-5-7-25(8-6-10)30(2,27)28/h3-4,9-10H,5-8H2,1-2H3,(H3,21,22,23,24)
InChIKey:
JRNJNYBQQYBCLE-UHFFFAOYSA-N

引用这个纪录

CBID:5722 http://www.chembase.cn/molecule-5722.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
5-(2,3-difluoro-6-methoxybenzoyl)-2-N-(1-methanesulfonylpiperidin-4-yl)pyrimidine-2,4-diamine
IUPAC传统名
5-(2,3-difluoro-6-methoxybenzoyl)-2-N-(1-methanesulfonylpiperidin-4-yl)pyrimidine-2,4-diamine
别名
R547
(4-AMINO-2-{[1-(METHYLSULFONYL)PIPERIDIN-4-YL]AMINO}PYRIMIDIN-5-YL)(2,3-DIFLUORO-6-METHOXYPHENYL)METHANONE
CAS号
741713-40-6
PubChem SID
160969149
99444565
PubChem CID
6918852

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
S2688 external link 加入购物车 请登录

理论计算性质

理论计算性质

JChem ALOGPS 2.1
Acid pKa 14.5448065  质子受体
质子供体 LogD (pH = 5.5) 0.3789153 
LogD (pH = 7.4) 0.9363782  Log P 0.9526561 
摩尔折射率 108.6708 cm3 极化性 40.217087 Å3
极化表面积 127.51 Å2 可自由旋转的化学键
里宾斯基五规则 true 
Log P 1.57  LOG S -3.41 
溶解度 1.72e-01 g/l 

分子性质

分子性质

安全信息 药理学性质 产品相关信息 生物活性(PubChem)
保存条件
-20°C expand 查看数据来源
作用靶点
CDK 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

DrugBank DrugBank Selleck Chemicals Selleck Chemicals
DrugBank -  DB08094 external link
Drug information: experimental
Selleck Chemicals -  S2688 external link
Biological Activity
Description R547 is a potent and selective CDK inhibitor with Ki and IC50 of 1-3 nM and 80 nM respectively.
Targets CDK
IC50 80 nM [2]
In Vitro R547 identified as a diaminopyrimidine compound, which is a potent and selective ATP-competitive CDK inhibitor. R547 effectively inhibits CDK1/cyclinB, CDK2/cyclinE, and CDK4/cyclinD1(Ki=1–3nM) and is inactive(Ki>5,000nM) against a panel of >120 unrelated kinases. R547 effectively inhibits the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s <0.60 μm.="" r547="" reduces="" phosphorylation="" of="" the="" cellular="" retinoblastoma="" protein="" at="" specific="" cdk="" phosphorylation="" sites="" at="" the="" same="" concentrations="" that="" induced="" cell="" cycle="" arrest,="" suggesting="" a="" potential="" pharmaco="" dynamics="" marker="" for="" clinical="" use.="" r547="" inhibits="" the="" proliferation="" of="" tumor="" cell="" lines="" and="" is="" active="" in="" all="" 19="" cell="" lines="" tested="" irrespective="" of="" tissue="" of="" origin,="" multidrug="" resistance="" (mdr),="" p53,="" or="" retinoblastoma="" status.="">[1] R547 possessing both 5-and 6-fluoro substitution culminated in an Inhibitor with low, single-digit nanomolar potency against the CDKs(Ki=0.001,0.003,and 0.001 μM for CDK1,CDK2, and CDK4,respectively) and excellent cellular potency (IC50=0.08 μM,HCT116 cell line). [2]
In Vivo R547 administered with oral and i.v. dosing in multiple established human tumor significantly inhibits tumor activity(P < 0.01).="" r547="" administered="" orally="" at="" dose="" of="" 40="" mg/kg="" daily="" in="" colon,="" lung,="" breast,="" prostate,="" and="" melanoma="" human="" tumor="" xenograft="" models="" shows="" significant="" tgi="" (79–99%).="" r547="" is="" equally="" efficacious="" (tgi,="" 61–95%)="" when="" dosed="" with="" 40="" mg/kg="" i.v.="" once="" weekly.="" these="" doses="" of="" r547="" are="" not="" toxic="" and="" did="" not="" result="" in="" body="" weight="" loss.="" r547="" does="" not="" show="" signs="" of="" overt="" toxicity="" during="" the="" course="" of="" the="" 3-week="" study="" and="" any="" gross="" pathology="" at="" necropsies="" done="" at="" the="" end="" of="" the="" studies.="">[1] R547 inhibits tumor growth up to 95% in the HCT116 human colorectal tumor xenograft model in nude mice . R547 causes significant TGI in all of the models tested when dosed orally and i.v. at or below the maximum tolerated dose. R547 inhibits phosphorylation of retinoblastoma protein in tumors at the efficacious exposures in tumor xenograft models, providing a pharmacodynamic biomarker for clinical use. R547 reported here suggests that this is a promising molecule for evaluation in the treatment of solid tumors. [2]
Clinical Trials R547 is currently in Phase I clinical trial for the treatment of cancer.
Features
References
[1] Rodriguez A , et al. Mol Cancer Ther, 2006, 5(11), 2644-2658.
[2] Chu XJ, et al. J Med Chem, 2006, 49(22), 6549-6560.
[3] Berkofsky-Fessler W, et al. Mol Cancer Ther, 2009, 8(9), 2517-2525.

参考文献

参考文献

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专利

专利

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