Linaclotide

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Linaclotide
Linaclotide structure.svg
Linaclotide structure. A 2D line-angle schematic of linaclotide (sequence CCEYCCNPACTGCY).[1] The phenolic ring of terminal tyrosine (Y) is in the lower left corner. Exaggerated bond lengths emphasize 3 disulfide (-S—S-) bonds between 6 cysteines (C's).
Clinical data
Trade names Linzess
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C59H79N15O21S6
Molar mass 1526.74 g/mol
3D model (Jmol)
 NYesY (what is this?)  (verify)

Linaclotide (marketed under the trade name Linzess in the US and Mexico, and as Constella in Canada[2] and many other countries[3]) is an oligo-peptide agonist of guanylate cyclase 2C. It was approved by the FDA in August 2012 and by the European Medicines Agency[4] for the treatment in adults of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation.[5]

Background[edit]

Medical need[edit]

The National Institutes of Health (NIH) estimate that as many as 20% of Americans may experience irritable bowel syndrome (IBS); approximately one-third of those, as many as 10 million Americans, experience constipation-predominant IBS (IBS-C), that is, IBS with constipation often accompanied by abdominal pain.[verification needed][citation needed] Laxatives can assist with constipation but do not treat pain, while opiates that are often prescribed to treat pain can aggravate constipation.[citation needed] While low-cost laxatives and pain killers would likely be tried first, linaclotide targets both associated conditions in a once-daily pill.[citation needed][6]

Structure[edit]

Linaclotide is a peptide mimic of endogenous guanylin and uroguanylin.[7][8] It is a synthetic tetradecapeptide (14 amino acid peptide) with the sequence CCEYCCNPACTGCY by one-letter abbreviation,[citation needed] or by three-letter abbreviation:[9]

H–Cys1–Cys2Glu3Tyr4–Cys5–Cys6Asn7Pro8Ala9–Cys10Thr11Gly12–Cys13–Tyr14–OH

However, the actual structure of linaclotide is not full specified without the three disulfide (R-S-S-R) bonds it contains, which are between Cys1 and Cys6, between Cys2 and Cys10, and between Cys5 and Cys13;[9] these are shown in exaggerated fashion in the line-angle graphic showing the chemical bonds within and between each amino acid (and their stereochemistries, see the infobox, above right), and are represented using a one-letter abbreviations in the following additional schematic:[citation needed]

Linaclotide schematic.svg

Mechanism of action[edit]

Linaclotide, like the endogenous guanylin and uroguanylin it mimics, is an agonist that activates the cell surface receptor of guanylate cyclase 2C (GC-C).[7][10][8] The medication binds to the surface of the intestinal epithelial cells.[10] Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses.[7] Activation of GC-C increases cyclic guanosine monophosphate (cGMP).[10] Elevated cGMP stimulates secretion of chloride and bicarbonate and water into the intestinal lumen, mainly by way of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel activation.[10][11] This results in increased intestinal fluid and accelerated transit.[10] By elevating cGMP, linaclotide is also considered to reduce activation of colonic sensory neurons, reducing pain;[10][12] and activates colonic motor neurons, which increases smooth muscle contraction and thus promotes bowel movements.[citation needed]

Related therapeutics[edit]

Plecanatide, a drug marketed under the name Trulance, was approved by the FDA in January 2017 for the treatment of chronic idiopathic constipation (CIC), and is likewise an agonist of guanylate cyclase, except with hexadecapeptide structure.[13]

Clinical trials[edit]

The FDA approval of linaclotide was based on four large randomized trials, two for each indication: IBS-C and CIC.[10] The approved dose for constipation-predominant irritable bowel syndrome (IBS-C) is 290 micrograms daily.[5][8] The approved dose for chronic idiopathic constipation (CIC) is 145 mcg daily; no benefit was seen in CIC by using 290 micrograms instead of 145 mcg daily.[10] In both situations, the most common side effect was diarrhea.[10]

In IBS-C, the phase III randomized double-blind clinical trials both showed some improvement in pain and constipation with the medication in comparison to placebo.[10]:11–13 Pain reduction started in the first week on the medication, with further improvement seen by weeks six to nine.[10]

In CIC, some effect on bowel habits was seen during the first week of treatment, reaching its maximum within that interval. Similarly, the effect returned toward baseline within one week of discontinuing the medication.[10]:13f[12]:Fig.2B An open-label safety study in CIC using linaclotide for up to a year found diarrhea to be the most frequently reported adverse event.[12]

Pharmacokinetics and pharmacodynamics[edit]

Systemic absorption of the globular tetradecapeptide is minimal.[7][12]

Chemistry[edit]

A study in discovery synthesis reported that 2 of 14 strategies available to synthesize linaclotide were successful—the successful ones involving trityl protection of all cysteines, or trityl protection of all cysteines except Cys1 and Cys6, which were protected with tert-butyl groups. The study also reported that solution-phase oxidation (disulfide formation) was advisable over solid-supported synthesis for linaclotide, and that the Cys1–Cys6 disulfide bridge was the most favored energetically.[9]

Distribution and licensing[edit]

Under a partnership agreement announced in 2007 between Forest Laboratories and Microbia (as Ironwood Pharmaceuticals was then known), Forest would pay $70 million in licensing fees towards the development of linaclotide, with profits shared between the two companies.[14] Distribution rights in the United States will be shared with Forest Laboratories, with Almirall distributing linaclotide in Europe and Astellas Pharma in Asia.[6]

See also[edit]

References[edit]

  1. ^ Oh, See Arr (August 17, 2011). "Macrocycle Milestone for Ironwood Pharma". The Haystack. Retrieved 11 February 2017 – via CENBlog.org. 
  2. ^ Constella (linaclotide) [product monograph]. Vaughan, Ontario, Canada: Forest Laboratories Canada Inc; May 2014.
  3. ^ [1][dead link]
  4. ^ Yu, Siegfried W.B.; Rao, Satish S.C. (11 February 2017). "Advances in the management of constipation-predominant irritable bowel syndrome: the role of linaclotide". Therap Adv Gastroenterol. 7 (5): 193–205. doi:10.1177/1756283X14537882. PMC 4107700Freely accessible. PMID 25177366. 
  5. ^ a b "Press Announcements - FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation". fda.gov. Retrieved 11 February 2017. 
  6. ^ a b Pollack, Andrew (September 13, 2010). "Drug for Irritable Bowel Achieves Goals in Trial". The New York Times. Retrieved September 14, 2010. 
  7. ^ a b c d Hussain ZH, Everhart K, Lacy BE (2015). "Treatment of Chronic Constipation: Prescription Medications and Surgical Therapies". Gastroenterol Hepatol (NY). 11 (2): 104–114, esp. 108f. PMC 4836568Freely accessible. PMID 27099579. 
  8. ^ a b c Love, Bryan L.; Johnson, Audrey; Smith, Lisa S. (2014). "Linaclotide: A Novel Agent For Chronic Constipation and Irritable Bowel Syndrome". American Journal of Health-System Pharmacy. 71 (13): 1081–1091. doi:10.2146/ajhp130575. ISSN 1079-2082. PMID 24939497. 
  9. ^ a b c Góngora-Benítez M; Tulla-Puche J; Paradís-Bas M; Werbitzky O; Giraud M & Albericio F (2011). "Optimized Fmoc solid-phase synthesis of the cysteine-rich peptide linaclotide" (PDF). Biopolymers (Peptide Science). 96 (1): 69–80. doi:10.1002/bip.21480. PMID 20560145. Retrieved February 10, 2017. 
  10. ^ a b c d e f g h i j k l Linzess package insert, Allergan, Plc, revised November 2015. Accessed August 18, 2016.
  11. ^ Yu SW, Rao SS (2014). "Advances in the management of constipation-predominant irritable bowel syndrome: the role of linaclotide". Therap Adv Gastroenterol. 7 (5): 193–205. doi:10.1177/1756283X14537882. PMC 4107700Freely accessible. PMID 25177366. 
  12. ^ a b c d Corsetti M, Tack J (2013). "Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation". United European Gastroenterol J. 1 (1): 7–20. doi:10.1177/2050640612474446. PMC 4040778Freely accessible. PMID 24917937. 
  13. ^ "FDA approves Trulance for Chronic Idiopathic Constipation". FDA.gov. U.S. Food and Drug Administration. Retrieved 20 January 2017. 
  14. ^ FDA News Staff (September 17, 2007). "Daily International Pharma Alert". FDA News. 4 (182). Retrieved September 15, 2010. 

Further reading[edit]

External links[edit]