1020315-31-4

Basic information

• Product Name: PF-04457845
• Synonyms: PF-04457845;N-Pyridazin-3-yl-4-(3-{[5-(trifluoroMethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxaMide;N-3-Pyridazinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methylene]-1-piperidinecarboxamide;1-Piperidinecarboxamide, n-3-pyridazinyl-4-[[3-[[5-(trifluoromethyl)-2- pyridinyl]oxy]phenyl]methylene]-;N-pyridazin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methylidene]piperidine-1-carboxamide
• CAS NO: 1020315-31-4
• Molecular Formula: C₂₃H₂₀F₃N₅O₂
• Molecular Weight: 455.4324096
• Mol File: 1020315-31-4.mol
• Article Data: 2

Chemical Properties

• Boiling Point: 687.0±55.0 °C(Predicted)
• Appearance: /
• Density: 1.389±0.06 g/cm3(Predicted)
• Storage Temp.: room temp
• PKA: 12.72±0.20(Predicted)
• CAS DataBase Reference: PF-04457845(CAS DataBase Reference)
• NIST Chemistry Reference: PF-04457845(1020315-31-4)
• EPA Substance Registry System: PF-04457845(1020315-31-4)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 1020315-31-4(Hazardous Substances Data)

Usage

Biochem/physiol Actions

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.

Synthetic route

phenyl pyridazin-3-ylcarbamate (1020327-61-0) + 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (1020325-53-4) → PF-04457845 (1020315-31-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 19h; Product distribution / selectivity;	86%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 16h;	86%

2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (1020325-53-4) + ethyl pyridazin-3-ylcarbamate (76925-49-0) → PF-04457845 (1020315-31-4)

Conditions	Yield
With triethylamine In acetonitrile at 180℃; for 0.666667h; Product distribution / selectivity; microwave irradiation;

2-[3-(chIoromethyl)phenoxy]-5-(trifluoromethyl)pyridine (1020325-30-7) → PF-04457845 (1020315-31-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 16 h / 130 °C 2: potassium tert-butylate / tetrahydrofuran 3: hydrogenchloride; water / 1,4-dioxane 4: N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 20 °C View Scheme

[3-[[5-(trifluoromethyl)-2-pyridyl]oxy]phenyl]methanol (1020325-22-7) → PF-04457845 (1020315-31-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: thionyl chloride / dichloromethane / 2 h / 20 °C 2: 16 h / 130 °C 3: potassium tert-butylate / tetrahydrofuran 4: hydrogenchloride; water / 1,4-dioxane 5: N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 20 °C View Scheme

2-[3-(diethoxyphosphorylmethyl)phenoxy]-5-(trifluoromethyl)pyridine (1020325-38-5) → PF-04457845 (1020315-31-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium tert-butylate / tetrahydrofuran 2: hydrogenchloride; water / 1,4-dioxane 3: N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 20 °C View Scheme

3-Hydroxybenzyl alcohol (620-24-6) → PF-04457845 (1020315-31-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 90 - 95 °C 2: thionyl chloride / dichloromethane / 2 h / 20 °C 3: 16 h / 130 °C 4: potassium tert-butylate / tetrahydrofuran 5: hydrogenchloride; water / 1,4-dioxane 6: N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 20 °C View Scheme

2-chloro-5-trifluoromethylpyridine (52334-81-3) → PF-04457845 (1020315-31-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 90 - 95 °C 2: thionyl chloride / dichloromethane / 2 h / 20 °C 3: 16 h / 130 °C 4: potassium tert-butylate / tetrahydrofuran 5: hydrogenchloride; water / 1,4-dioxane 6: N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 20 °C View Scheme

Upstream product

• 52334-81-3 2-chloro-5-trifluoromethylpyridine 
• 620-24-6 3-Hydroxybenzyl alcohol 
• 1020325-38-5 2-[3-(diethoxyphosphorylmethyl)phenoxy]-5-(trifluoromethyl)pyridine 
• 1020325-22-7 [3-[[5-(trifluoromethyl)-2-pyridyl]oxy]phenyl]methanol 
• 1020325-30-7 2-[3-(chIoromethyl)phenoxy]-5-(trifluoromethyl)pyridine 
• 1020327-61-0 phenyl pyridazin-3-ylcarbamate 
• 1020325-53-4 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride 
• 76925-49-0 ethyl pyridazin-3-ylcarbamate 

Relevant articles and documents

Discovery of PF-04457845: A highly potent, orally bioavailable, and selective urea FAAH inhibitor

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. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for the treatment of inflammatory pain and other nervous system disorders. Herein, we report the discovery and characterization of a highly efficacious and selective FAAH inhibitor PF-04457845 (23). Compound 23 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH with high in vitro potency (kinact/Ki and IC50 values of 40300 M-1 s-1 and 7.2 nM, respectively, for human FAAH). Compound 23 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. Oral administration of 23 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Compound 23 is being evaluated in human clinical trials.