PF-04457845

Short Summary : FAAH inhibitor,potent and exquisitely selective

Category : Metabolism|FAAH

Purity : 0.98

CAS Number : 1020315-31-4

Formula : C23H20F3N5O2

Molecular Weight : 455.43

SMILE : C1CN(CCC1=CC2=CC(=CC=C2)OC3=NC=C(C=C3)C(F)(F)F)C(=O)NC4=NN=CC=C4

Solubility : Soluble in DMSO

Storage : Store at -20°C

Description : PF-04457845 Description:IC50: Kinact/Ki and IC50 values of 40300 M-1 s-1 and 7.2 nM, respectively, for human FAAH [1].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 (http://en.wikipedia.org/wiki/PF-04457845).In vitro: Mechanistic studies confirm that PF-04457845 is a time-dependent, covalent FAAH inhibitor that carbamylates FAAH’s catalytic serine nucleophile. PF-04457845 inhibits human FAAH with high potency and is exquisitely selective in vivo as determined by activity-based protein profiling. [2]. 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. [2]. 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.Reference:[1] Johnson DS, Stiff C, Lazerwith SE, Kesten SR, Fay LK, Morris M, Beidler D, Liimatta MB, Smith SE, Dudley DT, Sadagopan N, Bhattachar SN, Kesten SJ, Nomanbhoy TK, Cravatt BF, Ahn K. Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor. ACS Med Chem Lett. 2011;2(2):91-96.[2] Ahn K, Smith SE, Liimatta MB, Beidler D, Sadagopan N, Dudley DT, Young T, Wren P, Zhang Y, Swaney S, Van Becelaere K, Blankman JL, Nomura DK, Bhattachar SN, Stiff C, Nomanbhoy TK, Weerapana E, Johnson DS, Cravatt BF. 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;338(1):114-24.

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