Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide[3]. PF-04457845 selectively inhibits FAAH with an IC50 of 7.2 nM[3]. Men aged 18–55 years with cannabis dependence were treated with PF-04457845 (4 mg per day), and they showed reduced symptoms of cannabis withdrawal, lower self-reported cannabis use and lower urinary THC-COOH concentrations, compared with placebo group[4]. Osteoarthritis patients administrated with 4 mg q.d. PF-04457845 showed decreased FAAH activity by >96% and significantly increased 4 endogenous substrates (fatty acid amides). PF-04457845 was well tolerated in osteoarthritis patients, and there was no evidence of cannabinoid-type adverse events, but failed to induce effective analgesia[5].
作用机制
PF-04457845 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH.
Redafamdastat 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HEK293T cells
0.0040 µM (IC50)
30 minutes
Inhibition of FAAH activity
Science. 2017 Jun 9;356(6342):1084-1087
HEK293T cells
0.011 µM (IC50)
4 hours
Inhibition of FAAH activity
Science. 2017 Jun 9;356(6342):1084-1087
Rat FAAH (rFAAH)
1 nM to 10 µM
1 to 60 minutes
PF-04457845 inhibited rFAAH with high potency (kinact/Ki value of 32,400 M−1s−1; IC50 of 7.4 nM) via an irreversible mechanism.
J Pharmacol Exp Ther. 2011 Jul;338(1):114-24
Human FAAH (hFAAH)
5 to 625 nM
1 to 60 minutes
PF-04457845 inhibited hFAAH with high potency (kinact/Ki value of 40,300 M−1s−1; IC50 of 7.2 nM) via an irreversible mechanism (i.e., carbamylation of the catalytic serine nucleophile).
J Pharmacol Exp Ther. 2011 Jul;338(1):114-24
COS-7 cells
0.3 to 3000 nM
1, 3, or 24 hours
Evaluation of PF-04457845's inhibitory effect on human recombinant FAAH, showing that PF-04457845 exhibited potent FAAH inhibitory activity in COS-hFAAH cells.
Biochim Biophys Acta Mol Basis Dis. 2022 Oct 1;1868(10):166456
Rat FAAH (rFAAH)
7.4 nM (IC50)
60 min preincubation
Evaluate the inhibitory activity of PF-04457845 on rFAAH, showing high inhibitory potency
ACS Med Chem Lett. 2011 Feb 10;2(2):91-96
Human FAAH (hFAAH)
7.2 nM (IC50)
60 min preincubation
Evaluate the inhibitory activity of PF-04457845 on hFAAH, showing high inhibitory potency
ACS Med Chem Lett. 2011 Feb 10;2(2):91-96
HN12 (p53 mutant)
1 µM and 2 µM
Day 3 and Day 6
To evaluate the effect of FAAH inhibitor on the antitumor efficacy of cisplatin, results showed that FAAH inhibitor did not interfere with the antitumor effect of cisplatin on HN12 cells
Mol Pharmacol. 2023 Apr;103(4):230-240
HN30 (p53 wild-type)
1 µM and 2 µM
Day 3 and Day 6
To evaluate the effect of FAAH inhibitor on the antitumor efficacy of cisplatin, results showed that FAAH inhibitor did not interfere with the antitumor effect of cisplatin on HN30 cells
Mol Pharmacol. 2023 Apr;103(4):230-240
Redafamdastat 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Complete Freund’s adjuvant (CFA)-induced inflammatory pain model
Oral
0.003 to 10 mg/kg
Single administration, lasting 24 hours
PF-04457845 exhibited significant analgesic effects in the CFA model (minimum effective dose of 0.1 mg/kg), accompanied by near-complete inhibition of FAAH activity and sustained elevation of anandamide levels in the brain. Additionally, PF-04457845 at 10 mg/kg had no effect on motility, catalepsy, or body temperature.
J Pharmacol Exp Ther. 2011 Jul;338(1):114-24
Rats
Juvenile rats
Oral gavage
0.02 mg/kg
Daily for 7 days
To investigate the effects of developmental PF-04457845 exposure on behavior, results showed increased motor activity and social play behavior.
Neurotoxicology. 2020 Mar;77:127-136
Rat
Juvenile rat model
Oral
0.02 mg/kg
Once daily from postnatal day 10 to day 16
To investigate the inhibition of FAAH by PF-04457845 and its long-term effects on protein expression in the amygdala. Results showed that PF-04457845 significantly inhibited FAAH activity and led to differential expression of 142 proteins in the amygdala during adolescence (PND38), affecting glutamatergic and GABAergic signaling pathways.
Neurotoxicology. 2021 Jul;85:234-244
Mice
NMRI mice
Oral
0.03 and 0.1 mg/kg
Single dose
Evaluation of the pharmacodynamic and pharmacokinetic properties of PF-04457845 in mice, showing that PF-04457845 was detectable in both plasma and brain, with brain exposure approximately 10-fold lower than in plasma.
Br J Pharmacol. 2020 May;177(9):2123-2142
Mice
Chronic constriction injury (CCI) model
Intraperitoneal injection
0.05, 0.1, 0.5, and 1.0 mg/kg
Single dose, behavioral tests conducted 2 hours post-injection
To determine the dose-dependent effects of PF04457845 on CCI-induced thermal hyperalgesia and mechanical allodynia. Results showed that 1.0 mg/kg PF04457845 completely blocked both thermal hyperalgesia and mechanical allodynia in CCI mice.
Cells. 2023 Apr 27;12(9):1275
Rats
CFA-induced inflammatory pain model
Oral
0.1 mg/kg
Single dose, evaluated after 4 hours
Evaluate the analgesic effect of PF-04457845 in an inflammatory pain model, showing significant reduction in mechanical allodynia at 0.1 mg/kg dose
ACS Med Chem Lett. 2011 Feb 10;2(2):91-96
Rats
Sprague-Dawley rats
Oral
1 mg/kg
Single dose, 1 hour before tracer injection
Evaluate the inhibitory effect of PF-04457845 on FAAH, showing significant reduction of tracer uptake in all brain regions (37%–73% at 90 min)
Nucl Med Biol. 2012 Oct;39(7):1058-67
Human
Healthy volunteers
Oral
1, 4, or 20 mg
Single dose
To evaluate the inhibitory effect of PF-04457845 on FAAH activity in the human brain. Results showed that PF-04457845 inhibited ≥91% of FAAH activity at a dose of 1 mg.
J Cereb Blood Flow Metab. 2015 Nov;35(11):1827-35
Rat
Pain model
Oral
10 mg
Single dose
To evaluate the in vivo efficacy of PF-04457845 in a pain model, showing good efficacy.
CPT Pharmacometrics Syst Pharmacol. 2014 Jan 15;3(1):e91
Male Sprague-Dawley rats
Acute restraint stress model
Intraperitoneal (i.p.) or intracerebroventricular (i.c.v.)
10 mg/kg (systemic), 3 μg or 30 μg (intracerebroventricular)
Single dose, 2 hours before stress
To assess the effects of PF-04457845 on homeostatic feeding and stress-induced changes in food intake. Results showed that i.c.v. administration of 30 μg PF-04457845 attenuated stress-induced anorexia via CB1 receptors but reduced homeostatic feeding in unstressed animals through an unknown mechanism.
Br J Pharmacol. 2019 May;176(10):1524-1540
Mice
Complete Freund’s adjuvant (CFA)-induced arthritis model
Oral
1–30 mg/kg
Single administration on day 3, 7, or 14 after CFA injection
To evaluate the antihyperalgesic effects of PF-04457845 in a chronic inflammatory pain model. Results showed that PF-04457845 significantly reduced mechanical and thermal hyperalgesia at doses of 3–30 mg/kg, but was less effective than URB937.
Pharmacol Res. 2012 May;65(5):553-63
Sprague Dawley rats
Early-life inflammation model
Oral or intra-amygdala
1mg/kg (oral) or 10ng (intra-amygdala)
Single administration, testing window 4-6 hours post-administration
To evaluate the ameliorative effects of FAAH inhibitor on social behavior deficits induced by early-life inflammation. Results showed that PF-04457845 reversed LPS-induced social behavior deficits but had no significant effect on the control group.
Brain Behav Immun. 2016 Nov;58:237-247
C57BL/6 male mice
No specific model used
Intranasal, intraperitoneal, and oral
5 mg/kg
Every other day for 20 days for a total of 10 drug treatments
To evaluate the inhibitory effects of PF-04457845 on FAAH activity via different administration routes. Results showed that PF-04457845 potently inhibits FAAH regardless of the route selected.
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