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Purity: ≥98%
PF-04457845 (PF04457845) is a novel, highly potent and selective FAAH (fatty acid amide hydrolase) inhibitor with the potential for mananing pain and other nervous system disorders. It inhibits FAAH with IC50 values of 7.2±0.63 nM and 7.4±0.62 nM for hFAAH and rFAAH, respectively. Pharmacological blockade of FAAH has emerged as a potentially attractive strategy for augmenting endocannabinoid signaling and retaining the beneficial effects of cannabinoid receptor activation, while avoiding the undesirable side effects, such as weight gain and impairments in cognition and motor control, observed with direct cannabinoid receptor 1 agonists. PF-04457845 inhibits human FAAH with high potency (k(inact)/K(i) = 40,300 M(-1)s(-1); IC(50) = 7.2 nM) and is exquisitely selective in vivo as determined by activity-based protein profiling. Oral administration of PF-04457845 produced potent antinociceptive effects in both inflammatory [complete Freund's adjuvant (CFA)] and noninflammatory (monosodium iodoacetate) pain models in rats, with a minimum effective dose of 0.1 mg/kg (CFA model). PF-04457845 displayed a long duration of action as a single oral administration at 1 mg/kg showed in vivo efficacy for 24 h with a concomitant near-complete inhibition of FAAH activity and maximal sustained elevation of anandamide in brain. Significantly, PF-04457845-treated mice at 10 mg/kg elicited no effect in motility, catalepsy, and body temperature. Based on its exceptional selectivity and in vivo efficacy, combined with long duration of action and optimal pharmacokinetic properties, PF-04457845 is a clinical candidate for the treatment of pain and other nervous system disorders.
| Targets |
Redafamdastat inhibits FAAH using an irreversible, covalent method that involves carbamylation of the serine nucleophile in the FAAH active site. This mechanism has a high in vitro efficacy (IC50 value of 7.2 nM and kinact/Ki values of 40300 M-1s-1 for human FAAH, respectively). Relative to other members of the serine hydrolase superfamily, redafamdastat exhibits fine selectivity for FAAH, as shown by competitive activity-based protein analysis. At doses of 10 and 100 μM, redafamdastat completely inhibits FAAH in the human and mouse membrane proteome without causing off-target effects [1]. Redafamdastat has complete selectivity for FAAH, and its inhibition of other FP-reactive serine hydrolases in test tissues is not observed, even at 100 μM concentrations [2].
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| ln Vitro |
Redafamdastat inhibits FAAH using an irreversible, covalent method that involves carbamylation of the serine nucleophile in the FAAH active site. This mechanism has a high in vitro efficacy (IC50 value of 7.2 nM and kinact/Ki values of 40300 M-1s-1 for human FAAH, respectively). Relative to other members of the serine hydrolase superfamily, redafamdastat exhibits fine selectivity for FAAH, as shown by competitive activity-based protein analysis. At doses of 10 and 100 μM, redafamdastat completely inhibits FAAH in the human and mouse membrane proteome without causing off-target effects [1]. Redafamdastat has complete selectivity for FAAH, and its inhibition of other FP-reactive serine hydrolases in test tissues is not observed, even at 100 μM concentrations [2].
Redafamdastat (PF-04457845) exhibits high in vitro potency against FAAH, with a second-order rate constant (\(k_{\text{inact}}/K_i\)) of 40,300 M⁻¹s⁻¹ for human FAAH and 32,400 M⁻¹s⁻¹ for rat FAAH, indicating efficient irreversible inhibition. The IC\(_{50}\) values determined with a 60-minute preincubation are 7.2 nM for human FAAH and 7.4 nM for rat FAAH. [1] Competitive activity-based protein profiling (ABPP) using a rhodamine-tagged fluorophosphonate (FP) probe in human and mouse brain membrane and liver soluble proteomes demonstrates that Redafamdastat (PF-04457845) at concentrations up to 100 µM completely inhibits FAAH without affecting any other serine hydrolases, showing exquisite selectivity. In contrast, the reference compound URB597 showed off-target inhibition of several serine hydrolases under the same conditions. [1] The compound shows moderate inhibition of cytochrome P450 enzymes CYP2D6 (IC\(_{50}\) = 14.5 µM) and CYP3A4 (IC\(_{50}\) > 30 µM when tested with midazolam and testosterone as substrates), indicating a low potential for drug-drug interactions mediated by these isoforms. [1] |
| ln Vivo |
Oral administration of 0.1 mg/kg redafamdastat was found to be equally efficacious as 10 mg/kg naproxen in a rat model of inflammatory pain. Redafamdastat was administered orally, and four hours later, a minimum effective dosage (MED) of 0.1 mg/kg was found to considerably inhibit mechanical allodynia. Furthermore, Redafamdastat (oral) at 0.1 mg/kg reduces pain responses in a manner similar to that of naproxen (10 mg/kg), an NSAID [1]. Mice given oral redafamdastat at doses of 1 or 10 mg/kg showed full inhibition of FAAH, according to competitive activity-based protein profiling (ABPP) investigations [2].
Oral administration of Redafamdastat (PF-04457845) produced significant antihyperalgesic effects in a rat model of inflammatory pain induced by complete Freund's adjuvant (CFA). The minimum effective dose (MED) was 0.1 mg/kg (p.o.), which was comparable to the effect of naproxen at 10 mg/kg. Efficacy was observed at doses from 0.1 to 10 mg/kg, with the degree of pain response inhibition being similar across all efficacious doses, likely because near-complete FAAH inhibition is required for in vivo efficacy. [1] The robust in vivo efficacy was accompanied by near-complete inhibition of FAAH activity and concomitant elevations in anandamide and other fatty acid amide levels in brain and plasma. [1] |
| Enzyme Assay |
The potency of FAAH inhibitors was measured as the second-order rate constant \(k_{\text{inact}}/K_i\) using an enzyme-coupled assay with human and rat FAAH. This method involves preincubating the enzyme with varying concentrations of the inhibitor for different time periods, followed by addition of a substrate. The reaction progress is monitored, and data is analyzed to determine the inactivation rate. Unlike IC\(_{50}\) measurements, \(k_{\text{inact}}/K_i\) values are independent of preincubation time and substrate concentration and are considered the optimal potency metric for irreversible inhibitors. [1]
IC\(_{50}\) values were also determined using a standard assay protocol with a fixed 60-minute preincubation of the enzyme with the inhibitor before adding the substrate. [1] |
| Animal Protocol |
For the in vivo efficacy study in the CFA inflammatory pain model, rats were injected subcutaneously with complete Freund's adjuvant into the plantar surface of the hind paw. Mechanical allodynia was assessed by measuring the paw withdrawal threshold. After 5 days post-injection, when hypersensitivity was established, rats were orally administered Redafamdastat (PF-04457845) suspended in a methylcellulose vehicle. Doses tested were 0.1, 0.3, 1, 3, and 10 mg/kg. Pain responses were measured 4 hours after drug administration. The nonsteroidal anti-inflammatory drug naproxen (10 mg/kg, p.o.) was used as a positive control. [1]
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| ADME/Pharmacokinetics |
Redafamdastat (PF-04457845) exhibited moderate permeability across the monolayer membrane of MDCK cells (A→B: 15.2 × 10⁻⁶ cm/s; B→A: 20.2 × 10⁻⁶ cm/s) with a B/A ratio of 1.33, indicating the absence of significant P-glycoprotein-mediated efflux. [1] In rats, the compound showed low clearance (CL = 12 mL/min/kg), moderate volume of distribution (Vdss = 2.0 L/kg), and high oral bioavailability (F = 88%) after oral administration of a methylcellulose crystal suspension. [1] In dogs, the compound also showed low clearance (CL = 4 mL/min/kg), moderate volume of distribution (Vdss = 1.7 L/kg), and good oral bioavailability (F = 58%). [1] In vitro human liver microsomal stability assays showed that the half-life was 105 minutes at a protein concentration of 0.8 mg/mL. The predicted clearance rate in human blood based on in vitro data was 0.6 mL/min/kg. [1] The microsomal protein binding rate was 90%. [1]
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| Toxicity/Toxicokinetics |
Competitive active site proteomics (ABPP) analysis of human and mouse proteomes at concentrations up to 100 µM showed no off-target inhibition of other serine hydrolases except for fatty acid amide hydrolase (FAAH), indicating that the compound has high selectivity and low risk of mechanistic toxicity. [1]
In vitro studies in rat and human hepatocytes showed that the compound did not generate glutathione conjugates, suggesting that it is unlikely to produce active metabolites. [1] |
| References |
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| Additional Infomation |
PF-04457845 is being studied in the field of fear conditioning. PF-04457845 has also been used to treat Tourette syndrome and cannabis dependence. Redafamdastat (PF-04457845) is a benzylpiperidinidazineurene discovered through structure-based drug design to enhance the molecular rigidity within the FAAH acyl chain binding pocket, thereby improving its potency and physicochemical properties. It has a clog P value of 3.9 and a polar surface area of 80 Ų. [1] The compound acts as an irreversible inhibitor by forming a carbamate bond with the active site of FAAH serine (Ser241), resulting in persistent inactivation of the enzyme. [1] In preclinical pain models, the compound exhibits superior in vivo potency compared to earlier lead compounds (e.g., PF-3845) and standard anti-inflammatory drugs (e.g., naproxen). [1]
As of the time of this publication, Redafamdastat (PF-04457845) is undergoing human clinical trials to evaluate its potential for treating chronic pain and other neurological disorders. [1] |
| Molecular Formula |
C23H20F3N5O2
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|---|---|
| Molecular Weight |
455.4324
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| Exact Mass |
455.156
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| CAS # |
1020315-31-4
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| PubChem CID |
24771824
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| Appearance |
White to off-white solid powder
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| LogP |
3.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
33
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| Complexity |
680
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1=C([H])N=C(C([H])=C1[H])OC1=C([H])C([H])=C([H])C(=C1[H])/C(/[H])=C1/C([H])([H])C([H])([H])N(C(N([H])C2C([H])=C([H])C([H])=NN=2)=O)C([H])([H])C/1([H])[H])(F)F
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| InChi Key |
BATCTBJIJJEPHM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H20F3N5O2/c24-23(25,26)18-6-7-21(27-15-18)33-19-4-1-3-17(14-19)13-16-8-11-31(12-9-16)22(32)29-20-5-2-10-28-30-20/h1-7,10,13-15H,8-9,11-12H2,(H,29,30,32)
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| Chemical Name |
N-pyridazin-3-yl-4-[(3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl)methylidene]piperidine-1-carboxamide
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| Synonyms |
PF-04457845; PF-4457845; PF 04457845; PF 4457845; PF04457845; PF4457845.
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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 : ≥ 100 mg/mL (~219.57 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (6.04 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 27.5 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: ≥ 2.75 mg/mL (6.04 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 27.5 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: ≥ 2.75 mg/mL (6.04 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 | 2.1957 mL | 10.9786 mL | 21.9573 mL | |
| 5 mM | 0.4391 mL | 2.1957 mL | 4.3915 mL | |
| 10 mM | 0.2196 mL | 1.0979 mL | 2.1957 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.
 Selectivity profiling of PF-04457845 and URB597 by competitive ABPP.J Pharmacol Exp Ther.2011 Jul;338(1):114-24. |
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 Assessment of in vivo protein targets of alkyne analogs of PF-04457845 and URB597 by CC-ABPP.J Pharmacol Exp Ther.2011 Jul;338(1):114-24. |
 Antihyperalgesic effects of PF-04457845 in the CFA model of inflammatory pain in rats.J Pharmacol Exp Ther.2011 Jul;338(1):114-24. |
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