| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
PF-4136309 racemate (INCB8761; INCB-8761; PF4136309; PF-4136309), the racemic mixture of PF-4136309, is an orally bioavailable CCR2 (C-C Motif Chemokine Receptor 2) antagonist with anticancer activity. It inhibits CCR2 with IC50 values of 5.2 nM, 17 nM and 13 nM for human, mouse and rat CCR2, respectively.
| Targets |
CCR2
|
|---|---|
| ln Vitro |
In vitro activity: PF-4136309 exhibits potency in human chemotaxis activity (IC50 = 3.9 nM) and in the whole blood assay (IC50 = 19 nM). In mouse and rat chemotaxis assays, its IC50 values are 16 and 2.8 nM, respectively. With IC50 values of 3.3 and 0.5 nM, respectively, PF-4136309 exhibits potent inhibition of CCR2 mediated signaling events, including intracellular calcium mobilization and ERK (extracellular signal-regulated kinase) phosphorylation. With an IC50 of 20 μM, PF-4136309 suppresses the hERG potassium current in the hERG patch clamp assay. With IC50 values greater than 30 μM against the five main CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, PF-4136309 is not a cytochrome P450 (CYP) inhibitor. Moreover, at concentrations up to 30 μM, PF-4136309 is not a CYP inducer[1].
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| ln Vivo |
PF-4136309 (2 mg/kg) shows a moderate half-life (2.5 and 2.4 hours) following intravenous administration in both species. When taken orally, PF-4136309 (10 mg/kg) is quickly absorbed, with rats and dogs experiencing peak concentration times (Tmax) of 1.2 and 0.25 hours, respectively. When administering IV and po doses to both species, a comparable half-life is seen. In both species, PF-4136309 exhibits a high degree of oral bioavailability, measuring 78%[1].
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| ADME/Pharmacokinetics |
In vitro ADME (absorption, distribution, metabolism, and excretion) profiling revealed that 17 (INCB8761/PF-4136309) has a moderate permeability across Caco-2 monolayers with a value of 3.1 × 10–6 cm/s. In protein binding, 17 had a free fraction of 23% in human serum. When incubated with human liver microsomes, 17 exhibited a moderate intrinsic clearance, with a half-life (t1/2) of 89 min. When 17 was incubated with human S9 with or without NADPH and the cofactor glutathione, no glutathione adducts were detected. Compound 17 is not a cytochrome P450 (CYP) inhibitor, with IC50 values of >30 μM against five major CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Compound 17 is not a CYP inducer at concentrations up to 30 μM.
[1]
The pharmacokinetics of 17 (INCB8761/PF-4136309) was assessed in rats and dogs (Table 4). Following iv administration of 17, the total systemic clearance was moderate in rats but low in dogs. The apparent steady-state volume of distribution (Vss) followed the same trend as in clearance, with high Vss in rats and low Vss in dogs. As a result, 17 exhibited a moderate half-life in both species after iv administration (2.5 and 2.4 h). When administered orally, 17 was absorbed rapidly, with peak concentration time (Tmax) at 1.2 h for rats and 0.25 h for dogs. A similar half-life was observed in both species between iv dosing and po dosing. Compound 17 was well absorbed, with an oral bioavailability of 78% in both species.[1] |
| References |
ACS Med Chem Lett.2011 Oct 5;2(12):913-8.
|
| Additional Infomation |
The discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists was reported. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in vivo ADMET profile. INCB8761/PF-4136309 has entered human clinical trials.[1]
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| Molecular Formula |
C29H31N6O3F3
|
|---|---|
| Molecular Weight |
568.59004
|
| Exact Mass |
568.24
|
| Elemental Analysis |
C, 61.26; H, 5.50; F, 10.02; N, 14.78; O, 8.44
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| CAS # |
857679-55-1
|
| Related CAS # |
PF-4136309;1341224-83-6;(s)-PF-4136309;1372407-07-2
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| PubChem CID |
11192346
|
| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
712.2±60.0 °C at 760 mmHg
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| Flash Point |
384.5±32.9 °C
|
| Vapour Pressure |
0.0±2.4 mmHg at 25°C
|
| Index of Refraction |
1.626
|
| LogP |
2.1
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
41
|
| Complexity |
894
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
C1CN(C[C@H]1NC2CCC(CC2)(C3=NC=C(C=C3)C4=NC=CC=N4)O)C(=O)CNC(=O)C5=CC(=CC=C5)C(F)(F)F
|
| InChi Key |
ZNSVOHSYDRPBGI-CBQRAPNFSA-N
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| InChi Code |
InChI=1S/C29H31F3N6O3/c30-29(31,32)21-4-1-3-19(15-21)27(40)36-17-25(39)38-14-9-23(18-38)37-22-7-10-28(41,11-8-22)24-6-5-20(16-35-24)26-33-12-2-13-34-26/h1-6,12-13,15-16,22-23,37,41H,7-11,14,17-18H2,(H,36,40)/t22?,23-,28?/m0/s1
|
| Chemical Name |
N-[2-[(3S)-3-[[4-hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexyl]amino]pyrrolidin-1-yl]-2-oxoethyl]-3-(trifluoromethyl)benzamide
|
| Synonyms |
857679-55-1; INCB-8761; Benzamide,N-[2-[(3S)-3-[[4-hydroxy-4-[5-(2-pyrimidinyl)-2-pyridinyl]cyclohexyl]amino]-1-pyrrolidinyl]-2-oxoethyl]-3-(trifluoromethyl)-; Benzamide, N-[2-[(3S)-3-[[4-hydroxy-4-[5-(2-pyrimidinyl)-2-pyridinyl]cyclohexyl]amino]-1-pyrrolidinyl]-2-oxoethyl]-3-(trifluoromethyl)-; INCB8761 (PF-4136309);
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7587 mL | 8.7937 mL | 17.5874 mL | |
| 5 mM | 0.3517 mL | 1.7587 mL | 3.5175 mL | |
| 10 mM | 0.1759 mL | 0.8794 mL | 1.7587 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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