PF-8380

SKU: orb1226919

Description

Potent autotaxin inhibitor (IC50 = 2.8 nM in isolated enzyme assay; 101 nM in human whole blood). Modulates lysophosphatidic acid (LPA) levels in vivo and in vitro by directly inhibiting autotaxin; reduces LPA levels both in plasma and at site of inflammation. Orally available.

Key Properties

• CAS Number: 1144035-53-9
• MW: 478.33
• Purity: >98% (HPLC)
• Formula: C₂₂H₂₁Cl₂N₃O₅
• SMILES: O=C(N1CCN(CCC(C2=CC=C3NC(OC3=C2)=O)=O)CC1)OCC4=CC(Cl)=CC(Cl)=C4
• Target: PDE
• Solubility: DMSO: 95 mg/mL (198.6 mM)

Bioactivity

• In Vivo:
  The pharmacokinetic profile of PF-8380 is evaluated at an intravenous dose of 1 mg/kg and oral doses of 1 to 100 mg/kg out to 24 h. PF-8380 has mean clearance of 31 mL/min/kg, volume of distribution at steady state of 3.2 L/kg, and effective t1/2 of 1.2 h. Oral bioavailability is moderate, ranging from 43 to 83%. Plasma concentrations increased with single oral escalating doses, but Cmax increased at a rate that is approximately proportional to dose from 1 to 10 mg/kg and less than proportional to dose from 10 to 100 mg/kg. PF-8380 exposures estimated by area under the curve are approximately proportional to dose and linear up to 100 mg/kg. Plasma C16: 0, C18: 0, and C20: 0 LPA levels are measured immediately after collection. Maximal reduction of LPA levels is observed by the 3 mg/kg dose at 0.5 h with all LPA returning at or above baseline at 24 h. Treatment with 10 mg/kg PF-8380 increases tumor-associated vascularity modestly by 20% (P = 0.497). When compared to control, treatment of PF-8380 45 min before 4 Gy irradiation decreases vascularity by nearly 48% when compared to control (P = 0.031) and by 65% when compared to mice that received radiation alone (P = 0.011).
• In Vitro:
  PF-8380 also inhibits rat autotaxin with an IC50 of 1.16 nM with FS-3 substrate. Potency of PF-8380 is maintained when using enzyme produced from fetal fibroblasts used in combination with lysophosphatidyl choline (LPC) as a substrate. In human whole blood incubated with PF-8380 for 2 h, autotaxin is inhibited with an IC50 of 101 nM. Autotaxin (ATX), an enzyme with lysophospholipase D (lysoPLD) activity, catalyzes the production of lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Pre-treatment of GL261 and U87-MG cells with 1 μM PF-8380 followed by 4 Gy irradiation results in decreased clonogenic survival, decreases migration (33% in GL261; P=0.002 and 17.9% in U87-MG; P=0.012), decreases invasion (35.6% in GL261; P=0.0037 and 31.8% in U87-MG; P=0.002), and attenuates radiation-induced Akt phosphorylation.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

PF8380 | PF-8380 | PF 8380

Quick Database Links

Gene Symbol

PDE