| 规格 | 价格 | 库存 | 数量 |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg |
|
||
| Other Sizes |
|
| 靶点 |
AMPK α2β1γ1 (EC50 = 6.8 nM); AMPK α1β1γ1 (EC50 = 7 nM)
The target of PF-06409577 is adenosine monophosphate-activated protein kinase (AMPK), specifically acting as a direct activator of AMPK. [1] PF-06409577 is a direct activator of AMPK, with a preference for the β1 subunit of AMPK (α1β1γ1 isoform), [2] |
|---|---|
| 体外研究 (In Vitro) |
PF-06409577 激活 AMPK 亚型 α1β1γ1 和 α2β1γ1，EC50 值分别为 7.0 nM 和 6.8 nM，但针对 α1β2γ1/α2β2γ1/α2β2γ3 亚型 α1β1γ1 和 α2β1γ1 的活性明显较低，EC50 值大于 4000 nM[1].10 0 µM）主要人类细胞色素 P450 亚型的微粒体活性。
1. 在分子对接研究中，将PF-06409577对接至AMPK的α1β1γ1亚型。PF-06409577的吲哚母核相较于其在X射线晶体结构中的原始构象出现轻微偏转，且该化合物与AMPK α1β1γ1亚型的活性位点之间形成氢键，这是其能够直接激活AMPK的结构基础[2] |
| 体内研究 (In Vivo) |
PF-06409577 在糖尿病肾病临床前模型中表现出功效[1]。它在大鼠（血浆未结合部分，fu,p = 0.0044）、狗（fu,p = 0.028）、猴（fu,p = 0.032）和人（fu,p = 0.017）中表现出高血浆蛋白结合。静脉注射给药后，PF-06409577 在大鼠 (22.6 mL/min/kg)、狗 (12.9 mL/min/kg) 和猴子 (8.57 mL/min/kg) 中表现出中等的血浆清除率 (CLp)，并且分布良好稳态分布体积 (Vdss) 范围为 0.846-3.15 L/kg。当大鼠、狗和猴子口服给药时，0.5% 甲基纤维素悬浮液中的结晶 PF-06409577 很快被吸收（Tmax = 0.25-1.20 小时）。大鼠、狗和猴子的口服生物利用度 (F) 值分别为 15%、100% 和 59%。与其他临床前物种和人类相比，PF-06409577 在大鼠体内遭受更大程度的首过肠道葡萄糖醛酸化[2]。
|
| 酶活实验 |
PF-06409577 在 DMSO 中制备。将 PF-06409577 与完全磷酸化的 AMPK 在测定缓冲液中在室温下孵育 15 分钟，然后添加 PP2a，并在室温下再次孵育 60 分钟。在停止磷酸酶处理并开始激酶测定之前，添加冈田酸（最终 50 nM）、50 nM Cy-5 SAMS 肽和等于每种亚型 Km 的 ATP。反应再孵育 60 分钟后，通过向检测缓冲液中添加 10 mM EDTA 和 2 nM Eu-pACC 抗体来猝灭激酶反应。分别使用 320 nM 的激发和 665 和 615 nM 的发射测量来测量激酶活性。
|
| 细胞实验 |
PF-06409577 对人类和大鼠 α1β1γ1 亚型具有相似的效力。在针对其他受体、通道、PDE 和激酶的广泛筛选中，PF-06409577 表现出最小的脱靶药理学。 PF-06409577 在膜片钳测定 (100 µM) 中未显示出可检测到的 hERG 抑制作用，并且不是主要人细胞色素 P450 亚型的微粒体活性的抑制剂 (IC50>100 µM)。
|
| 动物实验 |
Rats: For 68 days, daily administration of ramipril in drinking water (1 mg/kg/day), PF-06409577 at 10, 30, or 100 mg/kg (p.o.), PF-249 at 3, 10, or 30 mg/kg (p.o.), or 0.5% methylcellulose (p.o.) is started and continued. After 14, 28, 42, and 60 days of dosing, all lean and obese rats have their 24-hour urine collected, and the volume is recorded. All rats receive a final dose on day 63 following a 16-hour overnight fast. One hour after the last dose, a 100 L tail vein blood sample is taken and processed to determine the total protein and insulin levels. Blood glucose is also measured using a glucometer. Isoflurane is then used to put each rat to sleep. The right kidney is collected and immediately freeze-clamped and transferred to liquid nitrogen storage; the left kidney is fixed in 10% formalin. Rats are then euthanized by exsanguination from the vena cava[1]
|
| 药代性质 (ADME/PK) |
Optimization of the core and aryl appendage of the lead compound (indazole acid) improved the oral absorption of PF-06409577, but no specific ADME parameters (such as absorption rate, distribution, metabolism, excretion, half-life, oral bioavailability, etc.) were described in the literature [1]
|
| 参考文献 | |
| 其他信息 |
1. PF-06409577 (chemical name: 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid) is an indole acid compound and a direct activator of AMPK. It was developed based on human genetic association data, with the potential to treat diabetic nephropathy. The discovery of this compound originated from an indazole amide hit compound identified by high throughput screening (HTS), and after truncation to its minimal pharmacophore to obtain an indazole acid lead compound, optimization of the core and aryl appendage improved oral absorption, ultimately leading to the identification of PF-06409577, which was advanced to first-in-human trials for the treatment of diabetic nephropathy [1]
2. AMPK is a protein kinase involved in maintaining cellular energy homeostasis, and direct β1-selective AMPK activators (including PF-06409577) have attracted renewed interest for the treatment of patients with diabetic nephropathy. In structure-based virtual screening and molecular docking studies, PF-06409577 was used as a reference compound for AMPK activator screening, and its binding mode to the α1β1γ1 isoform of AMPK was analyzed to guide the identification of novel β1-selective AMPK activators [2] |
| 分子式 |
C19H16CLNO3
|
|
|---|---|---|
| 分子量 |
341.79
|
|
| 精确质量 |
341.082
|
|
| 元素分析 |
C, 66.77; H, 4.72; Cl, 10.37; N, 4.10; O, 14.04
|
|
| CAS号 |
1467057-23-3
|
|
| 相关CAS号 |
|
|
| PubChem CID |
71748255
|
|
| 外观&性状 |
White to off-white solid powder
|
|
| LogP |
4.558
|
|
| tPSA |
73.32
|
|
| 氢键供体(HBD)数目 |
3
|
|
| 氢键受体(HBA)数目 |
3
|
|
| 可旋转键数目(RBC) |
3
|
|
| 重原子数目 |
24
|
|
| 分子复杂度/Complexity |
487
|
|
| 定义原子立体中心数目 |
0
|
|
| SMILES |
ClC1=CC2=C(C(C(=O)O)=CN2)C=C1C1C=CC(=CC=1)C1(CCC1)O
|
|
| InChi Key |
FHQXLWCFSUSXBF-UHFFFAOYSA-N
|
|
| InChi Code |
InChI=1S/C19H16ClNO3/c20-16-9-17-14(15(10-21-17)18(22)23)8-13(16)11-2-4-12(5-3-11)19(24)6-1-7-19/h2-5,8-10,21,24H,1,6-7H2,(H,22,23)
|
|
| 化学名 |
6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid
|
|
| 别名 |
|
|
| HS Tariff Code |
2934.99.9001
|
|
| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| 溶解度 (体外实验) |
|
|||
|---|---|---|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.08 mg/mL (6.09 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.08 mg/mL (6.09 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 2.08 mg/mL (6.09 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9258 mL | 14.6289 mL | 29.2577 mL | |
| 5 mM | 0.5852 mL | 2.9258 mL | 5.8515 mL | |
| 10 mM | 0.2926 mL | 1.4629 mL | 2.9258 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02286882 | Terminated | Drug: PF-06409577 or Placebo |
Healthy | Pfizer | November 2014 | Phase 1 |
(A) In vitro AMPK activity for selected AMPK heterotrimers (αβγ) activated with PF-06409577. (B) In vitro AMPK activity for selected AMPK heterotrimers (αβγ) activated with PF-249. (C) Ribbon representation of crystal structure of AMPKα1β1γ1 bound to PF-249. (D) Close-up view of the ligand-protein interface. (E) AMPKβsubunit levels in kidney tissue were measured by quantitative ELISA and plotted as percentage of AMPK heterotrimer containing theβ1 subunit.J Pharmacol Exp Ther.2017 May;361(2):303-311. |
|---|
(A) Western blot for AMPKβ1,β2, and pan-αin 293FT cells transfected with scrambled siRNA or siRNA targeting AMPKβ1. (B) ELISA quantification of ACC phosphorylation status in 293FT treated with siRNA and PF-06409577. (C) ELISA quantification of ACC phosphorylation status in 293FT treated with siRNA and PF-06409577.J Pharmacol Exp Ther.2017 May;361(2):303-311. |
(A) Cumulative urinary albumin excretion over a 24-hour period at multiple time points during a dosing study in obese ZSF1 rats treated with vehicle or PF-06409577; 10 or 11 animals per group. (B) Kidney AMPK phosphorylation status in terminal samples after 8 weeks of dosing, 1 hour after the last dose.J Pharmacol Exp Ther.2017 May;361(2):303-311. |
(A) Cumulative albumin excretion over a 24-hour period at multiple time points during a dosing study in ZSF1 rats treated with vehicle, PF-249, PF-06409577, or ramipril (1 mg/kg/d in drinking water); 12 animals per group. (B) Kidney AMPK phosphorylation status in terminal samples after 8 weeks of dosing, 1 hour after the last dose.J Pharmacol Exp Ther.2017 May;361(2):303-311. |
|---|
(A–C) Representative histology images of phospo-S6 (p-S6) reactivity in kidneys collected after 8 weeks of dosing vehicle or PF-06409577 to ZSF1 rats; 12 animals per group. Glomeruli are indicated by the arrows and stain area was quantified. (D) Quantitative measure of p-S6 stain area in glomeruli of five lean ZSF1 treated with vehicle, seven obese ZSF1 treated with vehicle, and seven obese ZSF1 animals treated with PF-06409577.J Pharmacol Exp Ther.2017 May;361(2):303-311. |
Quantitative PCR measurements of mRNA for (A)Col1a1, (B)Col4a1, (C)Nox4, and (D)Ppargc1ain kidney samples from animals treated with 3, 10, and 30 mg/kg PF-249, 100 mg/kg PF-06409577 (PF-577), or ramipril for 8 weeks; 8–10 animals per group. Significance compared with the obese vehicle group.J Pharmacol Exp Ther.2017 May;361(2):303-311. |
InvivoChem的所有产品仅用于作科学研究，不面向患者销售
Copyright 2020 InvivoChem LLC | All Rights Reserved 粤ICP备20063088号-1
COA
粤公网安备 44011102003439号
463611831
