货号:A319423 同义名: HIF-PHD Inhibitor II 产品仅供科研
JNJ-42041935 is a selective inhibitor of prolyl hydroxylase (PHD) with the pKis of 7.91 ± 0.04, 7.29 ± 0.05, and 7.65 ± 0.09 for PHD1, PHD2, and PHD3, respectively.
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产品名称 | HIF ↓ ↑ | HIF1 ↓ ↑ | PHD1 ↓ ↑ | PHD2 ↓ ↑ | PHD3 ↓ ↑ | 其他靶点 | 纯度 | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
KC7F2 |
+
HIF-1α, IC50: 20 μM |
+
HIF-1α, IC50: 20 μM |
99%+ | ||||||||||||||||
Lificiguat | ✔ | 99%+ | |||||||||||||||||
BAY 87-2243 | ✔ | 99%+ | |||||||||||||||||
PX-478 | ✔ | 98%+ | |||||||||||||||||
2-Methoxyestradiol | ✔ | 98% | |||||||||||||||||
CAY10585 |
++
HIF, IC50: 4.4 μM |
BCRP | 97% | ||||||||||||||||
DMOG | ✔ | 98% | |||||||||||||||||
FG-2216 |
++
PHD2, IC50: 3.9 μM |
99%+ | |||||||||||||||||
MK-8617 |
++++
PHD1, IC50: 1 nM |
++++
PHD2, IC50: 1 nM |
++++
PHD3, IC50: 14 nM |
99%+ | |||||||||||||||
1. 鼠标悬停在“+”上可以显示相关IC50的具体数值。"+"越多,抑制作用越强。2. "✔"表示该化合物对相应的亚型有抑制作用,但抑制强度暂时没有相关数据。 |
描述 | The hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, and ischemic and metabolic disease inter alia. Hypoxia-inducible factor-α (HIF-α) mediates the cells' transcriptional response to hypoxia. HIF-1α was shown to be increased in concentration in cells exposed to low oxygen and to bind to the promoter of the erythropoietin gene. HIF-1α forms a heterodimeric protein complex that includes HIF-1β and p300 and then binds to the hypoxia response element consensus sequences in the promoter region of hypoxia-responsive genes and up-regulates their expression. JNJ-42041935, was a potent, 2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes with pKi of 7.3 - 7.9. In a purified enzyme and cell-based assays, JNJ-42041935 was the most potent inhibitor of PHD2 181 - 417 with a pIC50 value of 7.0, also inhibited full-length PHD1, PHD2, and PHD3 enzymes with pKI values of 7.91, 7.29, and 7.65, respectively. The Km values for these isotypes for 2-OG were 0.80μM, 0.50μM, and 0.82 μM, respectively. It showed that JNJ-42041935 is a potent, 2-OG-competitive, reversible, and selective inhibitor of all three PHD isozymes. JNJ-42041935 was evaluated in the HIF-driven luciferase mouse model. The result showed that two hours after oral administration of 300 μmol/kg JNJ-42041935, the bioluminescence over the peritoneal area was increased by 2.2-fold relative to luciferase-treated vehicle controls, and six hours later, JNJ-42041935 stimulated erythropoietin secretion in vivo. Furthermore, administration of JNJ-42041935 (100 μmol/kg, p.o.) for 5 consecutive days resulted in a 2-fold increase in reticulocytes, an increase in hemoglobin by 2.3 g/dl, and an increase in the hematocrit of 9%. In a all, JNJ-42041935 is a new tool compound that is potent, 2-OG-competitive, reversible, and selective inhibitor of PHD enzymes that can be used to investigate the role of this target across a range of biological systems[2]. |
作用机制 | JNJ-42041935 binds to PHD2 enzyme in a 2-OG competitive mechanism of action. The acidic group present in JNJ-42041935 formed a salt bridge with Arg383. The lone pair of electrons on the nitrogen atom of the pyrazole and the benzimidizole bound to iron in the active site in a bidentate fashion. The other benzimidizole NH formed a hydrogen bond with a conserved water molecule that also participated in a hydrogen bond with Tyr303 of the protein[2]. |
Dose | Mice: 300 μmol/kg[1] (p.o.) |
Administration | p.o. |
计算器 | ||||
存储液制备 | 1mg | 5mg | 10mg | |
1 mM 5 mM 10 mM |
2.88mL 0.58mL 0.29mL |
14.42mL 2.88mL 1.44mL |
28.85mL 5.77mL 2.88mL |
CAS号 | 1193383-09-3 |
分子式 | C12H6ClF3N4O3 |
分子量 | 346.649 |
别名 | HIF-PHD Inhibitor II |
运输 | 蓝冰 |
存储条件 |
粉末 Sealed in dry,Store in freezer, under -20°C 液体 -20°C:3-6个月-80°C:12个月 |
溶解度 |
DMSO: 35 mg/mL(100.97 mM),注意:DMSO长时间开封后,会吸水并导致溶解能力下降,请避免使用长期开封的DMSO |
动物实验配方 |