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1020315-31-4

1020315-31-4 structure
1020315-31-4 structure
  • Name: PF-04457845
  • Chemical Name: N-pyridazin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methylidene]piperidine-1-carboxamide
  • CAS Number: 1020315-31-4
  • Molecular Formula: C23H20F3N5O2
  • Molecular Weight: 455.43200
  • Catalog: Signaling Pathways Metabolic Enzyme/Protease FAAH
  • Create Date: 2016-03-16 08:03:55
  • Modify Date: 2024-01-08 13:03:44
  • 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.
Name N-pyridazin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methylidene]piperidine-1-carboxamide
Synonyms CS-0868
N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide
UNII-H4C81M8YYW
PF-04457845
Description 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.
Related Catalog
Target

IC50: 7.2±0.63 nM (hFAAH), 7.4±0.62 nM (rFAAH)[1]
In Vitro PF-04457845 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-1s-1 and 7.2 nM, respectively, for human FAAH). PF-04457845 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. PF-04457845 completely inhibits FAAH in human and mouse membrane proteomes at both 10 and 100 μM with no off targets[1]. PF-04457845 is completely selective for FAAH, and none of the other FP-reactive serine hydrolases in the tested tissues are inhibited by PF-04457845 even at 100 μM[2].
In Vivo Oral administration of PF-04457845 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Oral administration of PF-04457845 causes a significant inhibition of mechanical allodynia measured after 4 h with a minimum effective dose (MED) of 0.1 mg/kg. Furthermore, at 0.1 mg/kg (p.o.), PF-04457845 inhibits the pain response to a comparable degree as the nonsteroidal anti-inflammatory drug naproxen at 10 mg/kg[1]. FAAH is confirmed to be completely inhibited in mice treated with PF-04457845 at 1 and 10 mg/kg p.o. by competitive activity-based protein profiling (ABPP) study[2].
Kinase Assay The IC50 values for the inhibition of hFAAH and rFAAH by PF-04457845 is determined. PF-04457845 is preincubated with FAAH for 60 min before initiating the reaction by the addition of the substrate oleamide. Mouse and human tissues are prepared and inhibitor selectivity is assessed by competitive activity-based protein profiling[1].
Animal Admin Rats[1] PF-04457845 is administered orally to male Sprague-Dawley rats (200g-250g) at the indicated dose (mg/kg) as a nanocrystalline suspension in 2% polyvinylpyrrolidone and 0.15% sodium dodecyl sulfate in H2O. The dose volume is 10 mL/kg. The Paw Withdrawal Threshold (PWT) is evaluated at 4 h post dose. PWT measurements are averaged and statistical comparisons between groups are made using analysis of variance and unpaired T-tests. Mice[2] Male C57BL6/J mice (7 weeks old; n=8) are treated with PF-04457845 (1 or 10 mg/kg in polyethyleneglycol 300 vehicle by oral administration in a volume of 4 mL/kg), the synthetic cannabinoid agonist WIN 55,212-2 (1 or 10 mg/kg in 18:1:1 saline/Emulphor/ethanol vehicle by intraperitoneal administration in a volume of 10 mL/kg), or the corresponding vehicle. Mice are evaluated for hypomotility, hypothermia, antinociceptive, and cataleptic effects at 4 h or 30 min after PF-04457845 or WIN 55,212-2 administration, respectively, using the tetrad tests except that catalepsy is assessed for 60 s instead of 10 s. Statistical analysis is performed using the Student's t test comparing each treatment group with vehicle.
References

[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.

[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.

[3]. Buntyn RW, et al. Inhibition of Endocannabinoid-Metabolizing Enzymes in Peripheral Tissues Following Developmental Chlorpyrifos Exposure in Rats. Int J Toxicol. 2017 Jan 1:1091581817725272.
Molecular Formula C23H20F3N5O2
Molecular Weight 455.43200
Exact Mass 455.15700
PSA 83.47000
LogP 4.75380
Hazard Codes Xi
RIDADR NONH for all modes of transport
1020327-61-0 structure

1020327-61-0
1020325-53-4 structure

1020325-53-4

~88%

1020315-31-4 structure

1020315-31-4
Literature: Johnson, Douglas S.; Stiff, Cory; Lazerwith, Scott E.; Kesten, Suzanne R.; Fay, Lorraine K.; Morris, Mark; Beidler, David; Liimatta, Marya B.; Smith, Sarah E.; Dudley, David T.; Sadagopan, Nalini; Bhattachar, Shobha N.; Kesten, Stephen J.; Nomanbhoy, Tyzoon K.; Cravatt, Benjamin F.; Ahn, Kay ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 2 p. 91 - 96
1020325-53-4 structure

1020325-53-4
76925-49-0 structure

76925-49-0

~%

1020315-31-4 structure

1020315-31-4
Literature: FAY, Lorraine Kathleen; Johnson, Douglas S.; Kesten, Suzanne Ross; Lazerwith, Scott E.; Morris, Mark Anthony; Stiff, Cory Michael; Meyers, Marvin Jay; Wang, Lijuan Jane Patent: US2008/261941 A1, 2008 ; Location in patent: Page/Page column 19 ;
1020325-30-7 structure

1020325-30-7

~%

1020315-31-4 structure

1020315-31-4
Literature: Johnson, Douglas S.; Stiff, Cory; Lazerwith, Scott E.; Kesten, Suzanne R.; Fay, Lorraine K.; Morris, Mark; Beidler, David; Liimatta, Marya B.; Smith, Sarah E.; Dudley, David T.; Sadagopan, Nalini; Bhattachar, Shobha N.; Kesten, Stephen J.; Nomanbhoy, Tyzoon K.; Cravatt, Benjamin F.; Ahn, Kay ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 2 p. 91 - 96
1020325-22-7 structure

1020325-22-7

~%

1020315-31-4 structure

1020315-31-4
Literature: Johnson, Douglas S.; Stiff, Cory; Lazerwith, Scott E.; Kesten, Suzanne R.; Fay, Lorraine K.; Morris, Mark; Beidler, David; Liimatta, Marya B.; Smith, Sarah E.; Dudley, David T.; Sadagopan, Nalini; Bhattachar, Shobha N.; Kesten, Stephen J.; Nomanbhoy, Tyzoon K.; Cravatt, Benjamin F.; Ahn, Kay ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 2 p. 91 - 96
620-24-6 structure

620-24-6

~%

1020315-31-4 structure

1020315-31-4
Literature: Johnson, Douglas S.; Stiff, Cory; Lazerwith, Scott E.; Kesten, Suzanne R.; Fay, Lorraine K.; Morris, Mark; Beidler, David; Liimatta, Marya B.; Smith, Sarah E.; Dudley, David T.; Sadagopan, Nalini; Bhattachar, Shobha N.; Kesten, Stephen J.; Nomanbhoy, Tyzoon K.; Cravatt, Benjamin F.; Ahn, Kay ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 2 p. 91 - 96
52334-81-3 structure

52334-81-3

~%

1020315-31-4 structure

1020315-31-4
Literature: Johnson, Douglas S.; Stiff, Cory; Lazerwith, Scott E.; Kesten, Suzanne R.; Fay, Lorraine K.; Morris, Mark; Beidler, David; Liimatta, Marya B.; Smith, Sarah E.; Dudley, David T.; Sadagopan, Nalini; Bhattachar, Shobha N.; Kesten, Stephen J.; Nomanbhoy, Tyzoon K.; Cravatt, Benjamin F.; Ahn, Kay ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 2 p. 91 - 96

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