| Identification | Back Directory | [Name]
PF-01247324 | [CAS]
875051-72-2 | [Synonyms]
133786
CS-2577
PF-1247324
PF-01247324
PF01247324;PF 01247324
6-amino-N-methyl-5-(2,3,5-trichlorophenyl)picolinamide
6-AMINO-N-METHYL-5-(2,3,5-TRICHLOROPHENYL)PYRIDINE-2-CARBOXAMIDE
2-PyridinecarboxaMide, 6-aMino-N-Methyl-5-(2,3,5-trichlorophenyl)-
6-AMINO-5-(2,3,5-TRICHLORO-PHENYL)-PYRIDINE-2-CARBOXYLIC ACID METHYLAMIDE | [Molecular Formula]
C13H10Cl3N3O | [MDL Number]
MFCD28156579 | [MOL File]
875051-72-2.mol | [Molecular Weight]
330.6 |
| Chemical Properties | Back Directory | [Boiling point ]
477.7±45.0 °C(Predicted) | [density ]
1.460±0.06 g/cm3(Predicted) | [storage temp. ]
room temp | [solubility ]
DMF: 30 mg/ml; DMSO: 30 mg/ml; Ethanol: 30 mg/ml; Ethanol:PBS (pH 7.2) (1:4): 0.2 mg/ml | [form ]
powder | [pka]
6.56±0.46(Predicted) | [color ]
white to beige | [InChI]
1S/C13H10Cl3N3O/c1-18-13(20)10-3-2-7(12(17)19-10)8-4-6(14)5-9(15)11(8)16/h2-5H,1H3,(H2,17,19)(H,18,20) | [InChIKey]
HPIUHDCRVYDAEJ-UHFFFAOYSA-N | [SMILES]
Clc1c(cc(cc1c2c(nc(cc2)C(=O)NC)N)Cl)Cl |
| Safety Data | Back Directory | [RIDADR ]
UN 2811 6.1 / PGIII | [WGK Germany ]
WGK 3 | [Storage Class]
6.1C - Combustible acute toxic Cat.3
toxic compounds or compounds which causing chronic effects | [Hazard Classifications]
Acute Tox. 3 Oral
Eye Irrit. 2
Skin Irrit. 2
STOT SE 3 |
| Hazard Information | Back Directory | [Description]
PF-01247324 is a blocker of the tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 (IC50 = 0.19 μM for human Nav1.8). It is selective for Nav1.8 over Nav1.1, Nav1.2, Nav1.5, and Nav1.7 channels (IC50s = 13, 12.8, 9, and 19 μM, respectively) as well as ether-a-go-go (ERG) potassium channels (IC50 = 30 μM). PF-01247324 blocks Nav1.8 channels in a VSP-FRET assay using HEK293 cells (IC50 = 2.6 μM). In vivo, PF-01247324 (100 mg/kg) reduces phase 2 flinching in a rat model of formalin-induced persistent pain. It increases latency to lift the inflamed paw and latency to paw withdrawal in rat models of carrageenan-induced thermal hyperalgesia and mechanical hyperalgesia induced by complete Freund''s adjuvant (CFA), respectively. | [Uses]
6-Amino-N-methyl-5-(2,3,5-trichlorophenyl)picolinamide is a Nav1.8 modulators that demonstrate efficacy in preclinical models of neuropathic and inflammatory pain, attenuates nociception and sensory neuron excitability. | [Biochem/physiol Actions]
In humans, PF-01247324 [6-amino-5-(2, 3, 5-trichloro-phenyl)-pyridine-2-carboxylic acid methylamide] prevents native tetrodotoxin-resistant (TTX-R) currents in dorsal root ganglion (DRG) neurons. | [Enzyme inhibitor]
This novel oral NaV1.8 blocker (FW = 330.59 g/mol) attenuates nociception and neuronal excitability by selectively targeting voltage-gated sodium transporter NaV1.8, with much weaker action against NaV1.1, NaV1.2, NaV1.4, NaV1.5, NaV1.6, and NaV1.7 transporters. PF-01247324 inhibited native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC50 = 331 nM) and in recombinantly expressed hNav 1.8 (IC50 = 196 nM), with 50-fold selectivity over recombinantly expressed TTX-R hNav 1.5 channels (IC50 ～ 10 μM) and 65-100 greater selectivity over TTX-sensitive (TTX-S) channels (IC50 ～ 10-18 μM). Native TTX-R currents in small diameter rodent DRG neurons were inhibited with an IC50 of 448 nM, and the block of both human recombinant Nav1.8 and TTX-R from rat DRG neurons was both frequency and statedependent. Unlike previously published NaV1.8 blockers, PF-01247324 demonstrates frequency-dependence, and off-target frequency-dependence at other sodium channel subtypes may reduce its selectivity window. The majority of small molecule sodium channel blockers interact at the local anesthetic binding site, which due to a high level of sequence homology across voltage-gated sodium channel subtypes seems an unlikely site for interaction of selective agents such as PF-01247324. The majority of small molecule sodium channel blockers interact at the local anesthetic binding site, which due to a high level of sequence homology across voltage-gated sodium channel subtypes seems an unlikely site for interaction of selective agents such as PF-01247324 | [in vivo]
Experiments n rodents demonstrates efficacy in both inflammatory and neuropathic pain models. PF-01247324 reduces phase 2 flinching by 37% at 100 mg/kg. There is a significant effect of 30 mg/kg of PF-01247324 in the rat model carrageenan-induced thermal hyperalgesia and in CFA-induced mechanical hyperalgesia at exposures of 0.218 and 0.126 μM respectively[1]. Mice that received PF-01247324 shows significant improvements in motor coordination and cerebellar-like symptoms compared to control[2]. | [IC 50]
Nav1.8 | [References]
[1] SHARAN K. BAGAL*. Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain[J]. ACS Medicinal Chemistry Letters, 2015, 6 6: 650-654. DOI: 10.1021/acsmedchemlett.5b00059
[2] ANDRESEN M. Faculty Opinions recommendation of A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability.[C]. 2015: 0. DOI: 10.3410/f.725328550.793503635 |
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