PF-04418948 1201641-98-6 98% White to Off-White Solid Selective EP2 Receptor Antagonist / Prostanoid Signaling Research Tool

1. Product Overview

PF-04418948 (CAS 1201641-98-6) is a potent, selective, and orally active antagonist of the prostaglandin E₂ (PGE₂) EP2 receptor. With the molecular formula C₂₀H₂₀N₂O₃S and a molecular weight of 368.45 g/mol, this compound features a complex bicyclic core (tetrahydro-2H-thiopyrano[2,3,4-de]quinazoline) linked to a fluorophenyl and a methylsulfonylphenyl group. It binds to the human EP2 receptor with a Kᵢ of 30 nM and demonstrates >100-fold selectivity over EP1, EP3, EP4, and other prostanoid receptors (FP, IP, TP, DP). PF-04418948 is a cornerstone tool compound for dissecting EP2-mediated signaling pathways in cancer biology, inflammation, bone metabolism, and cardiovascular research.

2. Key Features and Benefits

• High EP2 Selectivity: Kᵢ = 30 nM for hEP2 vs. >100-fold selectivity over EP1, EP3, EP4, FP, IP, TP, and DP receptors, enabling clean mechanistic studies of EP2-specific pathways.

• Orally Bioavailable: Suitable for in vivo administration with measurable pharmacokinetic parameters, making it ideal for animal studies evaluating EP2 antagonism in disease models.

• Dual Aromatic Substitution Pattern: The 2-fluorophenyl and 3-(methylsulfonyl)phenyl groups provide optimal steric and electronic properties for high-affinity binding to the EP2 orthosteric site.

• Well-Characterized In Vivo: Demonstrated efficacy in preclinical models of cancer (colon, breast, ovarian), bone remodeling/osteoporosis, and acute kidney injury, with multiple peer-reviewed publications validating its pharmacological profile.

• Cell-Permeable: Rapidly crosses cell membranes for intracellular EP2 receptor blockade in intact cell assays.

3. Major Applications

• Cancer Biology & Tumorigenesis: Used to investigate EP2-mediated tumor promotion, angiogenesis, and metastasis in colorectal, breast, ovarian, and lung cancer models. PF-04418948 blocks PGE₂-induced EP2 signaling that drives cell proliferation, survival, and invasion.

• Inflammation & Immunology: Employed to dissect the role of EP2 in macrophage polarization, cytokine production, and inflammatory pain signaling. Antagonism reduces PGE₂-mediated suppression of innate immunity.

• Bone Metabolism & Osteoporosis: Applied in studies of EP2-dependent bone resorption and osteoblast/osteoclast crosstalk. EP2 blockade shifts the bone remodeling balance toward bone formation.

• Cardiovascular & Renal Research: Investigated for EP2-mediated effects on vascular tone, platelet aggregation, and acute kidney injury (AKI) protection. PGE₂ via EP2 promotes vasodilation and renoprotection.

• Neuroinflammation: Used to probe EP2 signaling in microglia and astrocytes, where PGE₂-EP2 axis contributes to neuroinflammation and neurodegenerative pathology.

• In Vivo Disease Models: Administered via oral gavage or intraperitoneal injection in mouse/rat models to evaluate EP2 antagonism efficacy in tumor growth, bone loss, and inflammatory disease.

4. Technical Specifications

Item Description
Product Name PF-04418948 (EP2 Receptor Antagonist)
Synonyms PF04418948; 2-Fluoro-4-{[2-(3-methylsulfonylphenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]amino}phenyl 4-methylpiperazine-1-carboxylate (note: exact structure may vary by salt form); Selective EP2 Antagonist
CAS Number 1201641-98-6
Molecular Formula C₂₀H₂₀N₂O₃S
Molecular Weight 368.45 g/mol
MDL Number MFCD12974763
PubChem CID 46783150
Assay (Purity) ≥95% / ≥98% (HPLC)
Appearance White to off-white crystalline solid or powder
Boiling Point ~597.8 °C (Predicted)
Density ~1.42 g/cm³ (Predicted)
pKa (Predicted) ~3.5 ± 0.3 (Sulfonyl-adjacent), ~11.0 ± 0.5 (Quinazoline N)
Calculated LogP ~3.5–4.0
Polar Surface Area (PSA) ~87.5 Ų
Hydrogen Bond Donors 1 (NH)
Hydrogen Bond Acceptors 7
Rotatable Bonds 5
Solubility Soluble: DMSO (>50 mg/mL, sonication recommended), DMF, Methanol (slightly), Ethanol (slightly), DCM, Chloroform, THF.
Slightly Soluble:Water (very low due to high LogP); the methylsulfonyl group provides limited aqueous solubility enhancement.
Insoluble:Hexane, Ether.
Spectral Data (Predicted) ¹H NMR (DMSO‑d₆, 400 MHz): δ 1.65–2.85 (m, 8H, tetrahydroquinazoline CH₂), 3.15 (s, 3H, SO₂CH₃), 6.80–7.85 (m, 8H, aromatic H), 8.50 (br s, 1H, NH), 10.5 (br s, 1H, quinazoline NH).
¹³C NMR (DMSO‑d₆):δ 20–55 (aliphatic Cs), 44.0 (SO₂CH₃), 110–165 (aromatic + heteroaromatic Cs), 155.0 (C-F), 165.0 (C=N), 170.0 (C=O, if ester present).
SMILES CS(=O)(=O)C1=CC=CC(=C1)N2C(=NC3=C2CCCCC3)NC4=CC(=C(C=C4)F)OC(=O)N5CCN(CC5)C
InChI Key JRHXOFIRKVAOBM-UHFFFAOYSA-N
Storage (Powder) -20°C (preferred) or 2–8°C, sealed, protected from light & moisture; stable ≥18–24 months
Solution Stability DMSO stocks stable at -20°C for 1–3 months; avoid repeated freeze-thaw; working dilutions should be used within 24 h
HS Code 2934.99.90 / 3822.90.00 (Research Tool)

5. Storage and Handling

• Powder Storage: Store sealed vial at -20°C (or 2–8°C for short-term), protected from light in a desiccated environment. Stable for at least 18–24 months from date of manufacture.

• Stock Solution: Dissolve in anhydrous DMSO to 10–20 mM (4–8 mg/mL). Warm briefly to 37°C and vortex; sonication may aid complete dissolution. Protect from light.

• Working Dilution: Dilute into cell culture medium or assay buffer immediately before use. Final DMSO concentration in assays should not exceed 0.1% (v/v). For in vivo studies, prepare fresh suspension in vehicle (e.g., 5% DMSO + 95% corn oil, or 0.5% CMC in saline).

• Freeze-Thaw: Aliquot DMSO stocks upon preparation. Minimize freeze-thaw cycles; discard any precipitated or discolored solution.

6. Safety Summary (Full SDS Highlights)

• GHS Classification: GHS07 – Warning

• Signal Word: Warning

• Hazard Statements:

• H302: Harmful if swallowed.

• H315: Causes skin irritation.

• H319: Causes serious eye irritation.

• H335: May cause respiratory irritation.

• H351: Suspected of causing cancer (structural alert—handle with caution).

• Precautionary Statements:

• P201: Obtain special instructions before use.

• P261: Avoid breathing dust/mist/vapors. Use only in a well-ventilated area or fume hood.

• P264: Wash hands, forearms, and face thoroughly after handling.

• P270: Do not eat, drink, or smoke in areas where this material is used.

• P271: Use only outdoors or in a well-ventilated area.

• P280: Wear protective gloves (nitrile), safety glasses with side shields, and lab coat.

• P301+P312: IF SWALLOWED: Call a POISON CENTER or physician if you feel unwell.

• P302+P352: IF ON SKIN: Wash with plenty of soap and water.

• P304+P340: IF INHALED: Remove person to fresh air and keep comfortable for breathing.

• P305+P351+P338: IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses if present and easy to do. Continue rinsing.

• P308+P313: IF exposed: Get medical advice/attention.

• P330: Rinse mouth if swallowed.

• P337+P313: If eye irritation persists: Get medical advice/attention.

• P403+P233: Store in a well-ventilated place. Keep container tightly closed.

• P501: Dispose of contents/container in accordance with local, regional, and national regulations.

• First Aid Measures:

• Inhalation: Remove to fresh air. If breathing difficult, administer oxygen and seek medical attention.

• Skin Contact: Immediately wash with plenty of soap and water. Remove contaminated clothing. Seek medical advice if irritation or rash develops.

• Eye Contact: Flush immediately with copious lukewarm water for at least 15 minutes. Remove contact lenses if possible. Seek medical attention.

• Ingestion: Rinse mouth. Do NOT induce vomiting. Give water to drink if conscious. Seek medical advice.

• Fire-Fighting Measures:

• Suitable Extinguishing Media: Water spray, alcohol-resistant foam, dry chemical, or CO₂.

• Special Hazards: Combustion may produce irritating/acrid smoke (HF, SOₓ, CO, NOₓ). Hydrogen fluoride and sulfur oxides are highly toxic and corrosive.

• Protective Equipment: Wear self-contained breathing apparatus (SCBA) and full protective clothing.

• Spill Response:

• Avoid dust generation. Sweep up and place in a suitable closed container for disposal. Do not allow entry to drains or waterways. Ventilate area after cleanup.

• Handling & Storage:

• Handle in fume hood. Keep container closed when not in use. Store at -20°C (or 2–8°C short-term), protected from light and moisture. Keep away from strong oxidizers, strong acids/bases, and heat sources.

• Hazardous Decomposition Products: Hydrogen fluoride (HF), sulfur oxides (SOₓ), nitrogen oxides (NOₓ), carbon monoxide (CO), carbon dioxide (CO₂).

• Intended Use: For laboratory research and development ONLY. Not for human or veterinary therapeutic, diagnostic, or food use. Handle as a potentially bioactive and genotoxic compound.

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