| In Vitro | In vitro activity: PF-3845 selectively inhibits FAAH by carbamylating FAAH's serine nucleophile. PF-3845 is a highly potent, selective and irreversible inhibitor of FAAH with Ki of 230 nM, it showed little activity against FAAH2. Structurally, PF-3845 is a biaryl ether piperidine. It inhibits FAAH by a covalent, irreversible mechanism involving carbamylating FAAH's catalytic S241 nucleophile. PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury.
Kinase Assay: PF-3845 is a selective fatty acid amide hydrolase (FAAH) inhibitor (Ki = 0.23 μM); showing negligible activity against FAAH2. |
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| In Vivo | PF-3845 treated mice (10 mg/kg, i.p.) shows rapid and complete inactivation of FAAH in the brain, as judged by competitive activity-based protein profiling (ABPP) with the serine hydrolase-directed probe fluorophosphonate (FP)-rhodamine. PF-3845 shows a long duration of action up to 24 hour. PF-3845-treated mice also shows dramatic (>10-fold) elevation in brain levels of AEA and other NAEs (N-pamitoyl ethanolamine [PEA] and N-oleoyl ethanolamine [OEA]). FAAH is AEA-degrading enzyme fatty acid amide hydrolase. PF-3845 (1–30 mg/kg, oral administration [p.o.]) causes a dose dependent inhibition of mechanical allodynia with a minimum effective dose (MED) of 3 mg/kg (rats are analyzed at 4 hour post dosing with PF-3845). At higher doses (10 and 30 mg/kg), PF-3845 inhibits pain responses to an equivalent, if not greater, degree than the nonsteroidal anti-inflammatory drug naproxen (10mg/kg, p.o.). PF-3845 (10 mg/kg, i.p.) significantly reverses LPS-induced tactile allodynia, but doesn't modify paw withdrawal thresholds in the saline-injected paw. |
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