875051-72-2

Usage

Uses

Used in Pharmaceutical Industry:
PF-01247324 is used as a pain management agent for the treatment of persistent pain. Its high selectivity for Nav1.8 channels makes it a promising candidate for the development of targeted therapies with reduced side effects compared to traditional pain medications.
Used in Neurological Research:
PF-01247324 is used as a research tool to study the role of Nav1.8 channels in pain perception and other neurological disorders. Its ability to selectively block Nav1.8 channels allows researchers to investigate the specific functions and mechanisms of this channel in various conditions.
Used in Drug Development:
PF-01247324 serves as a lead compound in the development of new drugs targeting Nav1.8 channels for the treatment of pain and other related conditions. Its high potency and selectivity make it an attractive starting point for the design and optimization of novel therapeutic agents.

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

Upstream product

• 178876-82-9 6-amino-5-bromo-pyridine-2-carboxylic acid methyl ester 
• 875051-78-8 N-(3-bromo-6-methylpyridin-2-yl)acetamide 
• 875051-81-3 C₈H₆BrN₂O₃^(1-)*K⁽¹⁺⁾ 
• 126325-46-0 2-amino-3-bromo-6-methyl-pyridine 
• 29682-15-3 methyl 5-bromopicolinate 
• 1616667-62-9 C₇H₆BrFN₂O 
• 1214336-44-3 methyl 5-bromo-6-fluoropyridine-2-carboxylate 
• 875051-79-9 methyl 6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-carboxylate 
• 74-89-5 methylamine 
• 212779-19-6 2,3,5-trichlorobenzeneboronic acid 
• 875051-80-2 6-amino-5-bromo-N-methyl-pyridine-2-carboxamide 

Relevant academic research and scientific papers

C-H FLUORINATION OF HETEROCYCLES WITH SILVER (II) FLUORIDE

The present invention provides compositions and methods for the selective C-H fluorination of nitrogen-containing heteroarenes with AgF2, which has previously been considered too reactive for practical, selective C-H fluorination. Fluorinated heteroarenes are prevalent in numerous pharmaceuticals, agrochemicals and materials. However, the reactions used to introduce fluorine into these molecules require pre-functionalized substrates or the use of F2 gas. The present invention provides a mild and general method for the C-H fluorination of nitrogen-containing heteroarene compounds to 2-fluoro-heteroarenes with commercially available AgF2. In various embodiments, these reactions occur at ambient temperature within one hour and occur with exclusive selectivity for fluorination at the 2-position. Exemplary reaction conditions are effective for fluorinating diazine heteroarenes to form a single fluorinated isomer.

Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain

Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain. (Chemical Presented).

Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution

We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride. A diverse array of functionalities can be installed because of the mild reaction conditions revealed for nucleophilic aromatic substitutions (SNAr) of the 2-fluoroheteroarenes. An evaluation of the rates for substitution versus the rates for competitive processes provides a framework for planning this functionalization sequence. This process is illustrated by the modification of a series of medicinally important compounds, as well as the increase in efficiency of synthesis of several existing pharmaceuticals.

Optimisation of permanganate oxidation and suzuki-miyaura coupling steps in the synthesis of a Nav1.8 Sodium channel modulator

The development is described of a viable kilo-scale synthesis of the Nav1.8 sodium channel modulator, N-methyl-6-amino- 5-(2,3,5-trichlorophenyl)pyridine-2-carboxamide(PF-1247324) in five steps, starting from 6-amino-5-bromo-2-picoline, in 33% overall yield. Two key steps required significant optimisation to improve yield and reproducibility. Oxidation of 6-acetamido-5-bromo-2-methylpyridine by permanganate to give the corresponding carboxylic acid derivative was improved by adding potassium dihydrogen phosphate, which moderated the reaction mixture pH and doubled the yield. The potassium fluoride-promoted Suzuki-Miyaura coupling between 2,4,5-trichlorophenylboronic acid and methyl 6-amino-5-bromopyridine-2- carboxylate, catalysed by tri(tert-butyl)phosphinepalladium (0), proceeded reliably to completion at room temperature in high yield when water was added. Anhydrous reaction mixtures reacted much more slowly, and 'wet' mixtures led to significant proto- deboronation in the absence of sufficient active catalyst. In the final step, amidation of the ester with methylamine gave PF-1247324.

PYRIDINE DERIVATIVES AS SODIUM CHANNEL MODULATORS

The present invention relates to compounds of the formula (I) and pharmaceutically acceptable salts and solvates thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds for the treatment of pain.

PYRIDINE DERIVATIVES

The present invention relates to compounds of the formula (I) and pharmaceutically acceptable salts and solvates thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds for the treatment of pain.