Linaclotide

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Linaclotide
Linaclotide structure.svg
Systematic (IUPAC) name
L-Cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-L-tyrosine cyclo(1-6),(2-10),(5-13)-tris(disulfide)
Clinical data
Trade names Linzess
Licence data US FDA:link
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Identifiers
CAS Registry Number 851199-59-2 YesY
ATC code A06AX04
PubChem CID: 16158208
IUPHAR/BPS 5017
ChemSpider 17314504 N
UNII N0TXR0XR5X YesY
KEGG D09355 YesY
Chemical data
Formula C59H79N15O21S6
Molecular mass 1526.74 g/mol
 N (what is this?)  (verify)

Linaclotide (marketed under the trade name Linzess and Constella) is a peptide agonist of the guanylate cyclase 2C. This compound reduces activation of colonic sensory neurons, reducing pain; and activates colonic motor neurons, which increases smooth muscle contraction and thus promotes bowel movements. It was approved by the FDA in August 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.[1] It was forecast by a market research firm to achieve blockbuster status by 2021.[2]

The National Institutes of Health (NIH) estimates that as many as 20% of Americans may experience signs of irritable bowel syndrome, with approximately one-third of those affected experiencing constipation often accompanied by abdominal pain, affecting as many as 10 million Americans. Laxatives can assist with constipation but do not treat pain, while use of opiates to treat pain can aggravate constipation. While low-cost laxatives and pain killers would likely be tried first, linaclotide targets both associated conditions in a once-daily pill.[3]

Clinical trials[edit]

In Phase I trials reported in January 2009 in The American Journal of Gastroenterology, it was found that 42 patients with chronic constipation who participated in the randomized, double-blind, placebo-controlled study experienced relief and that the medication was well tolerated.[4] In results of a first round of Phase III clinical trials announced in September 2010, Ironwood studied approximately 800 patients over 12 weeks who were given linaclotide or a placebo in a randomized double-blind trial. 34% of those receiving linaclotide experienced relief of pain and constipation, compared to 21% of patients who had taken the placebo. 50% of those receiving linaclotide saw a significant reduction in pain, versus 37% with the placebo, with pain reduction starting in the first week on the medication. 6% of patients left the study after experiencing diarrhea, the most commonly reported side effect.[3]

Distribution and licensing[edit]

Under a partnership agreement announced in 2007 between Forest Laboratories and Microbia (as Ironwood was then known), Forest would pay $70 million in licensing fees towards the development of linaclotide, with profits shared between the two companies.[5] Distribution rights in the United States will be shared with Forest Laboratories, with Almirall distributing linaclotide in Europe and Astellas Pharma in Asia.[3]

Chemistry[edit]

Linaclotide is a peptide consisting of 14 amino acids. The sequence is

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

There are three disulfide bonds: Between Cys1 and Cys6, between Cys2 and Cys10, and between Cys5 and Cys13.[6]

Linaclotide schematic.svg


References[edit]

  1. ^ "FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation". 30 Aug 2012. 
  2. ^ "Constella/Linzess Will Achieve Blockbuster Sales of $1.2 Billion in 2021 in the Irritable Bowel Syndrome Drug Market". 19 Dec 2012. 
  3. ^ a b c Pollack, Andrew. "Drug for Irritable Bowel Achieves Goals in Trial", The New York Times, September 13, 2010. Accessed September 14, 2010.
  4. ^ Jeffrey M Johnston , Caroline B Kurtz , Douglas A Drossman , Anthony J Lembo , Brenda I Jeglinski , James E MacDougall , Stephen M Antonelli & Mark G Currie . "Pilot Study on the Effect of Linaclotide in Patients With Chronic Constipation", The American Journal of Gastroenterology 104, 125–132 (1 January 2009) | doi:10.1038/ajg.2008.59. Accessed September 15, 2010.
  5. ^ Staff. "Daily International Pharma Alert", FDANews, September 17, 2007, Vol. 4 No. 182. Accessed September 15, 2010.
  6. ^ Albericio, F; Giraud, M; Gongora, M; Paradis, M; Tulla-Puche, J; Werbitzky, O. "Solid-Phase Synthesis of the Cys-rich Peptide Linaclotide" (PDF). 

External link[edit]

Linzess information Drugs com Retrieved 10-23-2013.