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Purity: ≥98%
PF-06747711 (PF06747711) is a novel, potent, selective, and orally bioactive retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) inverse agonist with anti-skin inflammatory activity. It activates RORγt with an IC50 of 4.1 nM. It was identified from a high-throughput screening and displayed promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified PF-06747711 as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration. Anti-skin inflammatory activity. The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine.
| Targets |
Compound 66, or PF-06747711, has an IC50 of 9.5 nM, which inhibits human Th17 cells' production of IL-17[1].
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| ln Vitro |
Compound 66, or PF-06747711, has an IC50 of 9.5 nM, which inhibits human Th17 cells' production of IL-17[1].
PF-06747711 is a potent and selective inverse agonist of RORC2, inhibiting coactivator peptide (SRC1-2) recruitment in a TR-FRET assay with IC₅₀ = 4.1 nM, and showing >25 μM IC₅₀ against RORA and RORB, indicating high isoform selectivity. In human primary Th17 cells, it inhibited IL-17A production with IC₅₀ = 9.5 nM (90% max inhibition). It also suppressed mRNA expression of IL-17A, IL-17F, IL-22, IL-26, and IL-23R in Th17 cells, while not affecting Th1/Th2 differentiation or cell viability at up to 10 μM. In a broad nuclear receptor profiling assay (trans-FACTORIAL, 48 receptors), only RORC2 showed >20% reduction at 1 μM; modest agonist effects were seen for ERRα and LXRα (fold increase ~1.3). The compound demonstrated slow dissociation from RORC2 (T₁/₂ ≈ 6 h in TR-FRET dissociation assay). [1] |
| ln Vivo |
In a dose-dependent way, PF-06747711 (10, 30, and 100 mg/kg, po, daily for 5 days) reduces ear edema in mice[1].
In a mouse imiquimod-induced skin inflammation model (psoriasis-like), oral administration of PF-06747711 (10, 30, 100 mg/kg once daily for 5 days) dose-dependently reduced ear swelling, with maximal inhibition of 46% at 100 mg/kg, comparable to anti-IL-17A antibody control. IL-17A protein levels in ear tissue were significantly reduced (70–72% at 30 and 100 mg/kg). The effect correlated with unbound plasma concentrations exceeding the in vitro IC₅₀ throughout the dosing interval. [1] |
| Enzyme Assay |
RORC2 TR-FRET coactivator recruitment assay: Purified N-terminal His-tagged RORC2 ligand-binding domain (LBD) was incubated with biotinylated coactivator peptide SRC1-2, streptavidin-APC, and europium-labeled anti-His antibody in assay buffer. Compounds were added and incubated for 3 h at room temperature. TR-FRET signal (ratio of 665 nm/615 nm) was measured; inverse agonists reduce signal by disrupting coactivator binding. IC₅₀ values were determined by nonlinear regression of dose–response curves. [1]
Radiologand SPA binding assay: Biotinylated RORC2 LBD was attached to streptavidin SPA beads and incubated with [³H]-25-hydroxycholesterol and test compounds overnight. Beads were centrifuged and radioactivity measured. IC₅₀ values were derived from dose-inhibition curves. [1] |
| Cell Assay |
Human Th17 cell IL-17 production assay: CD4+ T cells from healthy donors were differentiated into Th17 cells using anti-CD3/anti-CD28 beads and cytokines (IL-6, TGF-β, IL-1β, IL-21, IL-23) in 384-well plates. Compounds were added on day 2 and incubated for 6 days. IL-17A in supernatant was measured by ELISA. IC₅₀ values were calculated from dose–response curves. Cell viability was assessed using CellTiter-Glo. [1]
Mouse Th17 cell IL-17 production assay: CD4+ T cells from mouse spleen were differentiated with anti-mouse CD3/CD28 beads and cytokines (TGF-β, IL-6, IL-1β, IL-23). Compound was added and IL-17 measured after 4 days by electrochemiluminescence assay. [1] Gene expression analysis in human lymphocytes: After 6-day Th17 differentiation with compound treatment, RNA was extracted, reverse transcribed, and quantified by qPCR using TaqMan probes. Expression was normalized to housekeeping genes RPLP0 and B2M. [1] |
| Animal Protocol |
Animal/Disease Models: 8−10 week old female balb/c (Bagg ALBino) mouse[1]
Doses: 10, 30, and 100 mg/kg Route of Administration: PO daily over 5 days Experimental Results: Inhibited ear swelling, and caused a maximum inhibition of 46% at 100 mg/kg. Mouse imiquimod-induced skin inflammation model: Female Balb/c mice received topical 5% imiquimod cream on shaved back and ear for 3 consecutive days. PF-06747711 was administered orally once daily for 5 days as a spray-dried dispersion (25% HPMCAS-H polymer) in 0.5% methylcellulose, 0.5% HPMCAS-HF, and 20 mM Tris pH 7.4 buffer. Ear thickness was measured on day 5; ear tissue was homogenized for IL-17A protein measurement by ELISA. [1] Pharmacokinetic studies in rats, dogs, and mice: IV dosing was in 10% DMSO, 50% PEG400, 40% water (rats/mice) or similar vehicle for dogs. Oral dosing used either crystalline suspension in 0.5% methylcellulose or spray-dried dispersion formulation. Blood was collected over time, plasma precipitated with acetonitrile, and compound concentration determined by LC-MS/MS. [1] |
| ADME/Pharmacokinetics |
In human liver microsomes, PF-06747711 was poorly cleared (CL < 8 μL/min/mg). It had high passive permeability (Papp = 13.2 × 10⁻⁶ cm/s in RRCK cells) but low thermodynamic solubility (1.0 μM at pH 6.5). In rats, the intravenous clearance was 3.4 mL/min/kg with a half-life of 6 hours, and the oral bioavailability was 21% (crystallized) and 83% (spray-dried dispersant). In dogs, the clearance was 0.46 mL/min/kg with a half-life of 39 hours and the oral bioavailability was 73% (spray-dried dispersant). In mice, the clearance was 1.2 mL/min/kg. [1]
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| References | |
| Additional Infomation |
PF-06747711 was a lead compound obtained through high-throughput screening and optimized by combining structure-guided conformational restriction and lipophilic efficiency-driven design. The 4-trifluoromethyl group on the pyrrolopyridine core enhances its potency and metabolic stability. This compound is a selective RORC2 inverse agonist with the potential for oral treatment of autoimmune diseases such as psoriasis. [1]
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| Molecular Formula |
C26H26F3N5O2
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|---|---|
| Molecular Weight |
497.512156009674
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| Exact Mass |
497.203
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| Elemental Analysis |
C, 62.77; H, 5.27; F, 11.46; N, 14.08; O, 6.43
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| CAS # |
1892576-58-7
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| Related CAS # |
1892576-58-7;
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| PubChem CID |
118977746
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| Appearance |
White to off-white solid powder
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
36
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| Complexity |
863
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1C(=CN=C2C=1C(=CN2C)C1CCN(C(C(C)C)=O)CC1)NC(C1C=CC=C(C#N)C=1)=O)(F)F
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| InChi Key |
BIHPJIJLDNUDGH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H26F3N5O2/c1-15(2)25(36)34-9-7-17(8-10-34)19-14-33(3)23-21(19)22(26(27,28)29)20(13-31-23)32-24(35)18-6-4-5-16(11-18)12-30/h4-6,11,13-15,17H,7-10H2,1-3H3,(H,32,35)
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| Chemical Name |
3-Cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide
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| Synonyms |
PF06747711; PF 06747711; 1892576-58-7; PF-06747,711; 3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide; C26H26F3N5O2; MFCD31697703; PF-06747711
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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) |
DMSO : ~41.67 mg/mL (~83.76 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.18 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 2: ≥ 2.08 mg/mL (4.18 mM) (saturation unknown) in 10% DMSO + 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 20.8 mg/mL clear DMSO 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: ≥ 2.08 mg/mL (4.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0100 mL | 10.0500 mL | 20.1001 mL | |
| 5 mM | 0.4020 mL | 2.0100 mL | 4.0200 mL | |
| 10 mM | 0.2010 mL | 1.0050 mL | 2.0100 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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