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Purity: = 100%
PF-4136309 (formerly known as INCB8761) is a novel, potent, selective, and orally bioavailable small molecule CCR2 antagonist with IC50 values of 5.2 nM, 17 nM and 13 nM for human, mouse and rat CCR2, respectively. PF-4136309 demonstrated strong antagonistic activity against CCR2, remarkable selectivity, minimal hERG activity, and a superior ADMET profile both in vitro and in vivo. Trials on humans for PF-4136309 have begun. There are currently no published results from the phase I study of PF-4136309, which is being used to treat pancreatic neoplasms.
| Targets |
Human CCR2 ( IC50 = 5.2 nM ); Mouse CCR2 ( IC50 = 0.06 nM ); Rat CCR2 ( IC50 = 13 nM )
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| ln Vitro |
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| Enzyme Assay |
ERK5 kinase activity in vitro assay[1]
Kinase activity was determined in an assay volume of 40 μL in kinase buffer (50 mM Tris–HCl, pH 7.5, 0.1 mM EGTA, 1 mM 2-mercaptoethanol) containing 200 ng of pure active ERK5 and the indicated amount of inhibitor. Reaction started by adding 10 mM magnesium acetate, and 50 μM [γ-32P]-ATP (500 cpm/pmol) and 250 μM PIMtide (ARKKRRHPSGPPTA) as substrates. Assays were carried out for 20 min at 30 °C, terminated by applying the reaction mixture onto p81 paper and the incorporated radioactivity measured as described previously. Adaptor kinase assay of LRRK2 [G2019S][1] In vitro kinase assays were conducted at Invitrogen (Madison, WI) using the SelectScreen Kinase Profiling Service. |
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| Cell Assay |
In serum-free DMEM media, 500,000 HPBMCs are cultured with or without PF-4136309 and heated to 37 °C. For every well except the negative control, 400 μL of warmed 10 nM MCP-1 is added to the bottom chamber. The chamber lid is shut after an 8 micron membrane filter is positioned on top. Next, cells are inserted into the chamber lid's holes corresponding to the chamber wells beneath the filter membrane. The entire chamber is incubated for 30 minutes at 37 °C with 5% CO2. After that, the filter is carefully removed, the chamber lid is opened, and the cells are aspirated out. Wright Geimsa stain is applied after the filter has been allowed to air dry. Microscopy counts the filters. The number of cells that migrate to the bottom chamber in antagonist-containing wells and the number of cells that migrate to the bottom chamber in MCP-1 control wells are used to calculate the antagonist potency.
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| Animal Protocol |
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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] |
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| References | |||
| Additional Infomation |
The benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one core was discovered as a novel ERK5 (also known as MAPK7 and BMK1) inhibitor scaffold, previously. Further structure-activity relationship studies of this scaffold led to the discovery of ERK5-IN-1 (26) as the most selective and potent ERK5 inhibitor reported to date. 26 potently inhibits ERK5 biochemically with an IC₅₀ of 0.162 ± 0.006 μM and in cells with a cellular EC₅₀ for inhibiting epidermal growth factor induced ERK5 autophosphorylation of 0.09 ± 0.03 μM. Furthermore, 26 displays excellent selectivity over other kinases with a KINOMEscan selectivity score (S₁₀) of 0.007, and exhibits exceptional bioavailability (F%) of 90% in mice. 26 will serve as a valuable tool compound to investigate the ERK5 signaling pathway and as a starting point for developing an ERK5 directed therapeutic agent.[1]
We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. 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.[2] |
| Molecular Formula |
C₂₉H₃₁F₃N₆O₃
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| Molecular Weight |
568.59
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| Exact Mass |
568.241
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| Elemental Analysis |
C, 61.26; H, 5.50; F, 10.02; N, 14.78; O, 8.44
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| CAS # |
1341224-83-6
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| Related CAS # |
(s)-PF-4136309; 1372407-07-2; (Rac)-PF-4136309; 857679-55-1
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| PubChem CID |
11192346
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.027
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
41
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| Complexity |
894
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O[C@]1(CC[C@](CC1)([H])N[C@@H]2CN(CC2)C(CNC(C3=CC=CC(C(F)(F)F)=C3)=O)=O)C4=NC=C(C=C4)C5=NC=CC=N5
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| 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
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| 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
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (8.79 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 5 mg/mL (8.79 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 5 mg/mL (8.79 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (3.66 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 2.08 mg/mL (3.66 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 6: ≥ 2.08 mg/mL (3.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 7: ≥ 2.08 mg/mL (3.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 8: 10 mg/mL (17.59 mM) in 0.5% Methylcellulose/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01413022 | Completed | Drug: Oxaliplatin Drug: Irinotecan Drug: Leucovorin |
Pancreatic Neoplasms | Washington University School of Medicine |
April 2012 | Phase 1 |
| NCT01226797 | Terminated | Drug: Placebo Drug: PF-04136309 |
Female Patients With Overactive Bladder Syndrome |
Hepatitis C, Chronic | January 17, 2011 | Phase 2 |
ACS Med Chem Lett.2011 Oct 5;2(12):913-8. |
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ACS Med Chem Lett.2011 Oct 5;2(12):913-8. |
X-ray crystal structure of two molecules of compound17.ACS Med Chem Lett.2011 Oct 5;2(12):913-8. |
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