4-Aminopyridine

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4-Aminopyridine
4-aminopyridine.svg
4-aminopyridine-from-xtal-3D-bs-17.png
4-aminopyridine-from-xtal-3D-sf.png
4-aminopyridine sample.jpg
Names
Preferred IUPAC name
Pyridin-4-amine
Other names
4-Pyridinamine
4-Pyridylamine
Para-aminopyridine
fampridine (INN)
dalfampridine (USAN)
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.007.262 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 207-987-9
KEGG
MeSH 4-Aminopyridine
PubChem CID
UNII
  • InChI=1S/C5H6N2/c6-5-1-3-7-4-2-5/h1-4H,(H2,6,7) Yes check.svgY
    Key: NUKYPUAOHBNCPY-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C5H6N2/c6-5-1-3-7-4-2-5/h1-4H,(H2,6,7)
    Key: NUKYPUAOHBNCPY-UHFFFAOYAH
  • n1ccc(N)cc1
Properties
C5H6N2
Molar mass 94.1146 g/mol
Appearancecolourless solid
Melting point 155 to 158 °C (311 to 316 °F; 428 to 431 K)
Boiling point 273 °C (523 °F; 546 K)
polar organic solvents
Basicity (pKb)4.83 [1]
Pharmacology
N07XX07 ( WHO )
Oral
Pharmacokinetics:
96%
Legal status
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)
4-Aminopyridine 4-Aminopyridine.JPG
4-Aminopyridine

4-Aminopyridine (4-AP) is an organic compound with the chemical formula H2NC5H4N. It is one of the three isomeric aminopyridines. It is used as a research tool in characterizing subtypes of the potassium channel. It has also been used as a drug, to manage some of the symptoms of multiple sclerosis, [7] [8] and is indicated for symptomatic improvement of walking in adults with several variations of the disease. [9] It was undergoing Phase III clinical trials as of 2008, [10] and the U.S. Food and Drug Administration (FDA) approved the compound on January 22, 2010. [11] Fampridine is also marketed as Ampyra (pronounced "am-PEER-ah," according to the maker's website) in the United States by Acorda Therapeutics [11] [12] and as Fampyra in the European Union, Canada, and Australia. In Canada, the medication has been approved for use by Health Canada since February 10, 2012. [13]


Applications

In the laboratory, 4-AP is a useful pharmacological tool in studying various potassium conductances in physiology and biophysics.[ citation needed ] [14] [15] It is a relatively selective blocker of members of Kv1 (Shaker, KCNA) family of voltage-activated K+ channels. However, 4-AP has been shown to potentiate voltage-gated Ca2+ channel currents independent of effects on voltage-activated K+ channels. [16]

Convulsant activity

4-Aminopyridine is a potent convulsant and is used to generate seizures in animal models for the evaluation of antiseizure agents. [17]

Vertebrate pesticide

4-Aminopyridine is also used under the trade name Avitrol as 0.5% or 1% in bird control bait. It causes convulsions and, infrequently, death, depending on dosage. [18] The manufacturer says the proper dose should cause epileptic-like convulsions which cause the poisoned birds to emit distress calls resulting in the flock leaving the site; if the dose was sub-lethal, the birds will recover after 4 or more hours without long-term ill effect. [19] The amount of bait should be limited so that relatively few birds are poisoned, causing the remainder of the flock to be frightened away with a minimum of mortality. A lethal dose will usually cause death within an hour. [19] The use of 4-aminopyridine in bird control has been criticized by the Humane Society of the United States. [20]

Medical use

Fampridine
Clinical data
Trade names Ampyra, Fampyra, others
AHFS/Drugs.com Monograph
MedlinePlus a611005
License data
Identifiers
  • 1,4-dihydropyridin-4-imine
DrugBank
CompTox Dashboard (EPA)
ECHA InfoCard 100.007.262 OOjs UI icon edit-ltr-progressive.svg

Fampridine has been used clinically in Lambert–Eaton myasthenic syndrome and multiple sclerosis. It acts by blocking voltage-gated potassium channels, prolonging action potentials and thereby increasing neurotransmitter release at the neuromuscular junction. [21] The drug has been shown to reverse saxitoxin and tetrodotoxin toxicity in tissue and animal experiments. [22] [23] [24] [25] In calcium entry blocker overdose in humans, 4-aminopyridine can increase the cytosolic Ca2+ concentration very efficiently independent of the calcium channels. [22]

Multiple sclerosis

Fampridine has been shown to improve visual function and motor skills and relieve fatigue in patients with multiple sclerosis (MS). However, the effect of the drug is strongly established for walking capacity only. [26] Common side effects include dizziness, nervousness and nausea, and the incidence of adverse effects was shown to be less than 5% in all studies. [27] [6]

4-AP works as a potassium channel blocker. Strong potassium currents decrease action potential duration and amplitude, which increases the probability of conduction failure − a well documented characteristic of demyelinated axons. Potassium channel blockade has the effect of increasing axonal action potential propagation and improving the probability of synaptic vesicle release. A study has shown that 4-AP is a potent calcium channel activator and can improve synaptic and neuromuscular function by directly acting on the calcium channel beta subunit. [28]

MS patients treated with 4-AP exhibited a response rate of 29.5% to 80%. A long-term study (32 months) indicated that 80-90% of patients who initially responded to 4-AP exhibited long-term benefits. Although improving symptoms, 4-AP does not inhibit progression of MS. Another study, conducted in Brazil, showed that treatment based on fampridine was considered efficient in 70% of the patients. [29]

Spinal cord injury

Spinal cord injury patients have also seen improvement with 4-AP therapy. These improvements include sensory, motor and pulmonary function, with a decrease in spasticity and pain. [30]

Tetrodotoxin poisoning

Clinical studies have shown that 4-AP is capable of reversing the effects of tetrodotoxin poisoning in animals, however, its effectiveness as an antidote in humans has not yet been determined. [22] [23] [24]

Overdose

Case reports have shown that overdoses with 4-AP can lead to paresthesias, seizures, [31] and atrial fibrillation. [32]

Contraindications

4-aminopyridine is excreted by the kidneys. 4-AP should not be given to people with significant kidney disease (e.g., acute kidney injury or advanced chronic kidney disease) due to the higher risk of seizures with increased circulating levels of 4-AP.

Branding

The drug was originally intended, by Acorda Therapeutics, to have the brand name Amaya, however the name was changed to Ampyra to avoid potential confusion with other marketed pharmaceuticals. [33]

Four of Acorda's patents pertaining to Ampyra were invalidated in 2017 by the United States District Court for the District of Delaware and a fifth patent expired in 2018. [34] Since then, generic alternatives have been developed for the U.S. market. [35]

The drug is marketed by Biogen Idec in Canada as Fampyra [36] and as Dalstep in India by Sun Pharma. [37]

Research

Parkinson's disease

Dalfampridine completed Phase II clinical trials for Parkinson's disease in July 2014. [38] [ needs update ]

See also

Related Research Articles

<span class="mw-page-title-main">Lambert–Eaton myasthenic syndrome</span> Autoimmune disorder causing muscular weakness

Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs. It is also known as myasthenic syndrome, Eaton–Lambert syndrome, and when related to cancer, carcinomatous myopathy.

Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, and to reduce chest pain caused by angina pectoris.

A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no central nervous system (CNS) activity. They are often used during surgical procedures and in intensive care and emergency medicine to cause temporary paralysis. Spasmolytics, also known as "centrally acting" muscle relaxant, are used to alleviate musculoskeletal pain and spasms and to reduce spasticity in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxant, the term is commonly used to refer to spasmolytics only.

<span class="mw-page-title-main">BK channel</span> Family of transport proteins

BK channels (big potassium), are large conductance calcium-activated potassium channels, also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the cell membrane, hence their name, big potassium. These channels can be activated (opened) by either electrical means, or by increasing Ca2+ concentrations in the cell. BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability. BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization or increase in calcium levels.

<span class="mw-page-title-main">Quinidine</span> Antiarrythmic medication

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.

<span class="mw-page-title-main">Neuromuscular junction</span> Junction between the axon of a motor neuron and a muscle fiber

A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.

<span class="mw-page-title-main">Dantrolene</span> Chemical compound

Dantrolene sodium, sold under the brand name Dantrium among others, is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells. It achieves this by inhibiting Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors. It is the primary drug used for the treatment and prevention of malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia or drugs. It is also used in the management of neuroleptic malignant syndrome, muscle spasticity (e.g. after strokes, in paraplegia, cerebral palsy, or patients with multiple sclerosis), and poisoning by 2,4-dinitrophenol or by the related compounds dinoseb and dinoterb.

<span class="mw-page-title-main">End-plate potential</span> Voltages associated with muscle fibre

End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g. muscle, glial cells, neurons) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

<span class="mw-page-title-main">Diazoxide</span> Medication used to treat low blood sugar and high blood pressure

Diazoxide, sold under the brand name Proglycem and others, is a medication used to treat low blood sugar due to a number of specific causes. This includes islet cell tumors that cannot be removed and leucine sensitivity. It can also be used in refractory cases of sulfonylurea toxicity. It is generally taken by mouth.

<span class="mw-page-title-main">Neuromuscular-blocking drug</span> Type of paralyzing anesthetic including lepto- and pachycurares

Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.

<span class="mw-page-title-main">Cinnarizine</span> Antihistamine and calcium channel blocker medication

Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. It is prescribed for nausea and vomiting due to motion sickness or other sources such as chemotherapy, vertigo, or Ménière's disease. Cinnarizine is one of the leading causes of drug-induced parkinsonism.

<span class="mw-page-title-main">Agatoxin</span> Class of toxins

Agatoxins are a class of chemically diverse polyamine and peptide toxins which are isolated from the venom of various spiders. Their mechanism of action includes blockade of glutamate-gated ion channels, voltage-gated sodium channels, or voltage-dependent calcium channels. Agatoxin is named after the funnel web spider which produces a venom containing several agatoxins. There are different agatoxins. The ω-agatoxins are approximately 100 amino acids in length and are antagonists of voltage-sensitive calcium channels and also block the release of neurotransmitters. For instance, the ω-agatoxin 1A is a selective blocker and will block L-type calcium channels whereas the ω-agatoxin 4B will inhibit voltage sensitive P-type calcium channels. The μ-agatoxins only act on insect voltage-gated sodium channels.

<span class="mw-page-title-main">KCNA3</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein that in humans is encoded by the KCNA3 gene.

<span class="mw-page-title-main">KCNB1</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein that, in humans, is encoded by the KCNB1 gene.

<span class="mw-page-title-main">Flupirtine</span> Non-opioid analgesic

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Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.

<span class="mw-page-title-main">Potassium channel blocker</span> Several medications that disrupt movement of K+ ions

Potassium channel blockers are agents which interfere with conduction through potassium channels.

<span class="mw-page-title-main">Channel blocker</span> Molecule able to block protein channels, frequently used as pharmaceutical

A channel blocker is the biological mechanism in which a particular molecule is used to prevent the opening of ion channels in order to produce a physiological response in a cell. Channel blocking is conducted by different types of molecules, such as cations, anions, amino acids, and other chemicals. These blockers act as ion channel antagonists, preventing the response that is normally provided by the opening of the channel.

<span class="mw-page-title-main">Neosaxitoxin</span> Chemical compound

Neosaxitoxin (NSTX) is included, as other saxitoxin-analogs, in a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). The parent compound of PSTs, saxitoxin (STX), is a tricyclic perhydropurine alkaloid, which can be substituted at various positions, leading to more than 30 naturally occurring STX analogues. All of them are related imidazoline guanidinium derivatives.

References

  1. ↑ Albert A, Goldacre R, Phillips J (1948). "455. The strength of heterocyclic bases". Journal of the Chemical Society (Resumed): 2240–2249. doi:10.1039/JR9480002240.
  2. ↑ "Dalfampridine (Ampyra) Use During Pregnancy". Drugs.com. 22 June 2020. Retrieved 24 August 2020.
  3. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  4. ↑ "Fampyra 10 mg prolonged-release tablets - Summary of Product Characteristics (SmPC)". (emc). 15 August 2018. Retrieved 24 August 2020.
  5. ↑ "Ampyra- dalfampridine tablet, film coated, extended release". DailyMed. 20 December 2019. Retrieved 24 August 2020.
  6. 1 2 "Fampyra EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 24 August 2020.
  7. ↑ Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C (2002). Solari A (ed.). "Aminopyridines for symptomatic treatment in multiple sclerosis". The Cochrane Database of Systematic Reviews (4): CD001330. doi:10.1002/14651858.CD001330. PMC   7047571 . PMID   12804404.
  8. ↑ Korenke AR, Rivey MP, Allington DR (October 2008). "Sustained-release fampridine for symptomatic treatment of multiple sclerosis". The Annals of Pharmacotherapy. 42 (10): 1458–1465. doi:10.1345/aph.1L028. PMID   18780812. S2CID   207263182.
  9. ↑ "New Drugs: Fampridine". Australian Prescriber (34): 119–123. August 2011. Archived from the original on 2012-02-27.{{cite journal}}: CS1 maint: unfit URL (link)
  10. ↑ "Acorda Clinical Development and Product Pipeline". Acorda.
  11. 1 2 "FDA Approves Ampyra to Improve Walking in Adults with Multiple Sclerosis". U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on January 12, 2017.
  12. ↑ "Ampyra". National Multiple Sclerosis Society.
  13. ↑ "Notice of Decision for FAMPYRA". hc-sc.gc.ca. Archived from the original on 2012-05-02. Retrieved 2012-04-21.
  14. ↑ Stühmer W, Ruppersberg JP, Schröter KH, Sakmann B, Stocker M, Giese KP, et al. (November 1989). "Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain". The EMBO Journal. 8 (11): 3235–3244. doi:10.1002/j.1460-2075.1989.tb08483.x. PMC   401447 . PMID   2555158.
  15. ↑ Mathie A, Wooltorton JR, Watkins CS (January 1998). "Voltage-activated potassium channels in mammalian neurons and their block by novel pharmacological agents". General Pharmacology. 30 (1): 13–24. doi:10.1016/s0306-3623(97)00034-7. PMID   9457476.
  16. ↑ Wu ZZ, Li DP, Chen SR, Pan HL (December 2009). "Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit". The Journal of Biological Chemistry. 284 (52): 36453–36461. doi: 10.1074/jbc.M109.075523 . PMC   2794761 . PMID   19850918.
  17. ↑ Yamaguchi S, Rogawski MA (March 1992). "Effects of anticonvulsant drugs on 4-aminopyridine-induced seizures in mice". Epilepsy Research. 11 (1): 9–16. doi:10.1016/0920-1211(92)90016-m. PMID   1563341. S2CID   5772125.
  18. ↑ "EPA Reregistration Eligibility Decision for 4-aminopyridine" (PDF). U.S. Environmental Protection Agency. 27 September 2007. p. 23.
  19. 1 2 "What is Avitrol?". Avitrol Corporation, Tulsa, Oklahoma, US. Retrieved 15 August 2012.
  20. ↑ Brasted M (May 13, 2008). "Poisonous Solution: The Avitrol Problem". Humane Society of the United States. Archived from the original on December 25, 2008. Retrieved December 23, 2008.
  21. ↑ Judge SI, Bever CT (July 2006). "Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment". Pharmacology & Therapeutics. 111 (1): 224–259. doi:10.1016/j.pharmthera.2005.10.006. PMID   16472864.
  22. 1 2 3 van der Voort PH, Wilffert B, van Roon EN, Uges DR (July 2016). "4-Aminopyridine as a life-saving treatment in calcium channel antagonist intoxication". The Netherlands Journal of Medicine. 74 (6): 276. PMID   27571731.
  23. 1 2 Chang FC, Spriggs DL, Benton BJ, Keller SA, Capacio BR (July 1997). "4-Aminopyridine reverses saxitoxin (STX)- and tetrodotoxin (TTX)-induced cardiorespiratory depression in chronically instrumented guinea pigs". Fundamental and Applied Toxicology. 38 (1): 75–88. doi:10.1006/faat.1997.2328. PMID   9268607. S2CID   17185707.
  24. 1 2 Chen HM, Lin CH, Wang TM (November 1996). "Effects of 4-aminopyridine on saxitoxin intoxication". Toxicology and Applied Pharmacology. 141 (1): 44–48. doi:10.1006/taap.1996.0258. PMID   8917674.
  25. ↑ Octopus Envenomations at eMedicine.com
  26. ↑ Valet M, Quoilin M, Lejeune T, Stoquart G, Van Pesch V, El Sankari S, et al. (November 2019). "Effects of Fampridine in People with Multiple Sclerosis: A Systematic Review and Meta-analysis". CNS Drugs. 33 (11): 1087–1099. doi:10.1007/s40263-019-00671-x. PMID   31612418. S2CID   204543081.
  27. ↑ Fampyra: EPAR - Product Information (PDF), London: European Medicines Agency, 1 Jun 2017, archived from the original (PDF) on 11 February 2018, retrieved 11 Feb 2018
  28. ↑ Wu ZZ, Li DP, Chen SR, Pan HL (December 2009). "Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit". The Journal of Biological Chemistry. 284 (52): 36453–36461. doi: 10.1074/jbc.M109.075523 . PMC   2794761 . PMID   19850918.
  29. ↑ "Real-life experience with fampridine (Fampyra) for patients with multiple sclerosis and gait disorders". NeuroRehabilitation. August 1, 2016.
  30. ↑ Van Diemen HA, Polman CH, Koetsier JC, Van Loenen AC, Nauta JJ, Bertelsmann FW (June 1993). "4-Aminopyridine in patients with multiple sclerosis: dosage and serum level related to efficacy and safety". Clinical Neuropharmacology. 16 (3): 195–204. doi:10.1097/00002826-199306000-00002. PMID   8504436.
  31. ↑ Pickett TA, Enns R (March 1996). "Atypical presentation of 4-aminopyridine overdose". Annals of Emergency Medicine. 27 (3): 382–385. doi:10.1016/S0196-0644(96)70277-9. PMID   8599505.
  32. ↑ Johnson NC, Morgan MW (February 2006). "An unusual case of 4-aminopyridine toxicity". The Journal of Emergency Medicine. 30 (2): 175–177. doi:10.1016/j.jemermed.2005.04.020. PMID   16567254.
  33. ↑ Jeffrey S (January 22, 2010). "FDA Approves Dalfampridine to Improve Walking in Multiple Sclerosis". Medscape .
  34. ↑ "US courts invalidates Dalfampridine patents". Acorda.
  35. ↑ House DW (7 October 2019). "Supreme Court declines to hear Acorda appeal of adverse Ampyra patent ruling". Seeking Alpha. Retrieved 8 October 2019.
  36. ↑ "Fampyra Drug Monograph" (PDF). Health Canada Drug Product Database. Biogen Idec Canada Inc. 26 November 2014. Retrieved 10 October 2017.
  37. ↑ "Dalstep 10mg Registration Details". Registrationwala. Archived from the original on 2020-09-15. Retrieved 2018-11-25.
  38. ↑ Clinical trial number NCT01491022 for "A Randomized Trial to Evaluate Ampyra for Gait Impairment in Parkinson's Disease" at ClinicalTrials.gov
  39. ↑ Shinkichi Shimizu, Nanao Watanabe, Toshiaki Kataoka, Takayuki Shoji, Nobuyuki Abe, Sinji Morishita, Hisao Ichimura "Pyridine and Pyridine Derivatives" in "Ullmann's Encyclopedia of Industrial Chemistry" 2007; John Wiley & Sons: New York.
  40. ↑ Gardner TS, Wenis E, Lee J (1954). "The Synthesis of Compounds for the Chemotherapy of Tuberculosis. Iv. The Amide Function". The Journal of Organic Chemistry. 19 (5): 753. doi:10.1021/jo01370a009.
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