1020315-31-4

Redafamdastat (PF-04457845) is a highly efficacious and selective FAAH inhibitor with IC50 values is 7.2±0.63 nM and 7.4±0.62 nM for hFAAH and rFAAH, respectively.

PF-04457845 is a potent, orally active, irreversible inhibitor of fatty acid amide hydrolase (FAAH), the principle enzyme involved in the degradation of the endocannabinoid anandamide. PF-04457845 is a covalent inhibitor that carbamylates FAAH′s serine nucleophile. It was shown to be both potent and selective against other serine hydrolases. It has an IC50 value of 7.2 nM for human FAAH. The endocannabinoid system is a target for therapeutic pain relief. In a rat model of inflammatory pain, PF-04457845 produced significant reduction of inflammatory pain with efficacy comparable to that of naproxen at 10 mg/kg.

General procedure for the large-scale synthesis of N-(pyridazin-3-yl)-4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxamide in Example 5b: To a mixture of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-trifluoromethylpyridine hydrochloride (37.1 g, 0.10 mol, see Example 1b, step 5) and phenylpyridazin- 3-ylcarbamate (21.5 g, 0.10 mol, see Example 39, Step 1) in acetonitrile (400 mL) was added dropwise to a mixture of diisopropylethylamine (25.8 g, 0.20 mol). The solution was formed by stirring for 2 hours. The slightly cloudy solution was stirred at ambient temperature for 17 hours. It was poured into 2.5 L of stirred ice water. The resulting mixture was stirred for 1 hour. The solid was filtered out, rinsed with 300mL of water and pressed dry under suction. Dissolve it in 400mL of dichloromethane. The water was removed using a partition funnel, then the solution was dried with magnesium sulfate and concentrated under vacuum to about 50 mL. the viscous solution was diluted with 65 mL of ethyl acetate and then 85 mL of methyl tert-butyl ether. A solution was formed and then the solids began to separate. The crystalline mixture was kept at -10°C for 2 hours and filtered. The solid was rinsed with EtOAc:MTBE (40mL) and pressure dried under suction. It was further dried under vacuum at 40 °C for 7 h to give 30.3 g (66%) of product. The mother liquor was concentrated under vacuum to 19 g of a viscous oil. It was dissolved in 15 mL of ethyl acetate. The solution was diluted with 60 mL of methyl tert-butyl ether, inoculated and kept at 5°C for 18 hours. The crystallized solid was filtered out, rinsed with 10 mL of methyl tert-butyl ether and pressed dry under suction. 9.0 g (20%) of additional product was obtained. Total yield = 39.3 g (86%).

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[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. DOI:10.1021/ml100190t
[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. DOI:10.1124/jpet.111.180257
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