Description
PF-04457845 is a potent and exquisitely selective inhibitor of the enzyme fatty acid amide hydrolase (FAAH) with an IC50 value of 7.2 nM.
Product Overview
Fatty acid amide hydrolase or FAAH is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993. PF-04457845 is a potent and exquisitely selective inhibitor of the FAAH, and both analgesic and antiinflammatory effects in animal studies comparable to naproxen. Clinical trial: A clinical trial was approved to evaluate the pharmacology and tolerability of PF-04457845 in healthy subjects. Results showed that FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF-04457845. Mean fatty acid amide concentrations increased (3.5-to 10-fold) to a plateau and then were maintained following PF-04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF-04457845 on cognitive function. PF-04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated. These data indicated PF-04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.
Synonyms
PF 04457845; PF04457845
Molecular Formula
C23H20F3N5O2
Chemical Name
N-pyridazin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methylidene]piperidine-1-carboxamide
Solubility
Soluble in DMSO
Shipping Conditions
Evaluation sample solution: ship with blue ice. All other available size: ship with RT, or blue ice upon request
In vitro
Mechanistic studies confirm that PF-04457845 is a time-dependent, covalent FAAH inhibitor that carbamylates FAAHs catalytic serine nucleophile. PF-04457845 inhibits human FAAH with high potency and is exquisitely selective in vivo as determined by activity-based protein profiling.
In vivo
Oral administration of PF-04457845 produced potent antinociceptive effects in both inflammatory and noninflammatory pain models in rats, with a minimum effective dose of 0.1 mg/kg. PF-04457845 also 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. These data suggest PF-04457845 is a clinical candidate for the treatment of pain and other nervous system disorders.
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