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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.
| 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].
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| 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].
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| References |
[1]. Johnson DS, et al. Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor. ACS Med Chem Lett. 2011 Feb 10;2(2):91-96.
[2]. Ahn K, et al. Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain. J Pharmacol Exp Ther. 2011 Jul;338(1):114-24. [3]. Buntyn RW, et al. Inhibition of Endocannabinoid-Metabolizing Enzymes in Peripheral Tissues Following Developmental Chlorpyrifos Exposure in Rats. Int J Toxicol. 2017 Jan 1:1091581817725272 |
| Molecular Formula |
C23H20F3N5O2
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|---|---|
| Molecular Weight |
455.4324
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| CAS # |
1020315-31-4
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| SMILES |
O=C(N1CC/C(CC1)=C\C2=CC=CC(OC3=NC=C(C(F)(F)F)C=C3)=C2)NC4=NN=CC=C4
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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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| 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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