T3D2553

2594 T3D2553

4-Aminopyridine

Dalfampridine is a potassium channel blocker used to help multiple sclerosis patients walk. This is the first drug that was specifically approved to help with mobility in these patients. FDA approved on January 22, 2010. 4-Aminopyridine is an organic compound with the formula H2NC5H4N. The molecule is one of the three isomeric amines of pyridine. 4-Aminopyridine (4-AP) is prepared by the decarbonylation of pyridine-4-carboxyamide using sodium hypochlorite via the Hofmann rearrangement (L1082). 504-24-5

1727

C5H6N2

94.053100 Colourless solid (L1082).

157-161°C

273°C

74 g/L

Inhalation (T52, T14) ; oral (T52, T14) ; dermal (T52, T14) ; intravenous (T52, T14) Orally-administered dalfampridine is rapidly and completely absorbed from the gastrointestinal tract. Tmax, immediate release form = 1 hour; Tmax, extended release form = 3.5 hours; Cmax, 10 mg extended release = 17.3 - 21.6 ng/mL; Relative bioavailability of 10 mg extended-release tablets compared to aqueous oral solution = 96%

4-Aminopyridine blocks potassium channels and thereby increases acetylcholine, and possibly noradrenaline, release at nerve terminals (A316). In MS, axons are progressively demyelinated which exposes potassium channels. As a result, there is a leak of potassium ions which results in the repolarization of cells and a decrease in neuronal excitability. The overall impact is the impairment of neuromuscular transmission as it is harder to trigger an action potential. Dalfampridine inhibits voltage-gated potassium channels in the CNS to maintain the transmembrane potential and prolong action potential. In other words, dalfampridine works to make sure that the current available is high enough to stimulate conduction in demyelinated axons that are exposed in MS patients. Furthermore, it facilitates neuromuscular and synaptic transmission by relieving conduction blocks in demyelinated axons.

Not extensively metabolized by the liver therefore drugs effecting the cytochrome P450 enzyme system that are concomitantly administered with dalfampridine are not expected to interact with each other. 4-Aminopyridine is rapidly absorbed into the bloodstream from the gastrointestinal tract. It is readily broken down, or metabolized, in the liver into removable compounds excreted in urine. After intravenous and oral absoprtion, the metabolites were almost all excreted in the urine. It does not to concentrate or accumulate in skin. 4-Aminopyridine is excreted in urine and rapidly detoxified in the liver (T48, L1090). Metabolites include 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate and both are inactive. CYP2E1 is the enzyme responsible for 3-hydroxylation of dalfampridine. Route of Elimination: Almost all of the dose and its metabolites are completely eliminated by the kidneys after 24 hours. Urine (96%; 90% of total dose as unchanged drug); Feces (0.5%) Half Life: Immediate release form = 3.5 hours; Extended release form = 5.47 hours; LD50, oral, mouse = 19 mg/kg LD50, oral, rat = 21 mg/kg LD50: 20-29 mg/kg (Oral, Rat) (L1090) LD50: 3.7 mg/kg (Oral, Dog) (L1090) LD50: 326 mg/kg (Dermal, Rabbit) (L1090) No indication of carcinogenicity to humans (not listed by IARC).

Dalfampridine is a neurofunctional modifier that helps improve walking speed in patients with multiple sclerosis (MS). It is used primarily as a research tool, in characterizing subtypes of potassium channel, and has also been used to manage some of the symptoms of multiple sclerosis, for which it has orphan drug status in the United States and is undergoing Phase III clinical trials as of 2008 (L1082).

Conditions associated with overdose have included parasthesias, seizures, and atrial fibrillation. Human systemic effects by ingestion include hallucinations and distorted perceptions, and dyspnea (L1082).

Local irritation on contact with the skin, mucous membranes and cornea. Symptoms floowing ingestion include vomiting, Weakness, dizziness, disorientation, hyperexcitability, tremors, periorbital paresthesias and tonic-clonic seizures may be noted (T36, T52, T14). Administer charcoal as a slurry. Consider gastric lavage after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in Trendelenburg and left lateral decubitus position or by endotracheal intubation. Control any seizures first. Following inhalation, move patient to fresh air and monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with inhaled beta2 agonist and oral or parenteral corticosteroids. In case of eye exposure, irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If the exposure occurs through dermal exposure, remove contaminated clothing and wash exposed area thoroughly with soap and water. (T36)

2009-07-05T02:42:53Z

2026-03-26T20:10:17Z

4-Aminopyridine

C13728

34385

D015761

4-Aminopyridine

DB06637

6358

true

N=C1C=CNC=C1

C5H6N2

InChI=1S/C5H6N2/c6-5-1-3-7-4-2-5/h1-4H,(H2,6,7)

NUKYPUAOHBNCPY-UHFFFAOYSA-N

94.1145

94.053098202

Exogenous Solid

CHEMBL284348

1664

Fabio GARAVAGLIA, Alessandro BAROZZA, Jacopo ROLETTO, Paolo PAISSONI, “ONE-POT PROCESS FOR THE SYNTHESIS OF DALFAMPRIDINE.” U.S. Patent US20110319628, issued December 29, 2011.

CHEM002080

DTXSID0023870

NS00002207

1,4-dihydropyridin-4-imine