Linaclotide

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Linaclotide
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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 Number 851199-59-2 YesY
ATC code A06AX04 (WHO)
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
  • O=C(O)[C@@H](NC(=O)[C@H]4NC(=O)CNC(=O)[C@@H](NC(=O)[C@H]2NC(=O)[C@@H](NC(=O)[C@H]5N(C(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CSSC1)CSSC2)CCC(=O)O)Cc3ccc(O)cc3)CSSC4)CC(=O)N)CCC5)C)[C@H](O)C)Cc6ccc(O)cc6
  • InChI=1S/C59H79N15O21S6/c1-26-47(82)69-41-25-101-99-22-38-52(87)65-33(13-14-45(80)81)49(84)66-34(16-28-5-9-30(76)10-6-28)50(85)71-40(54(89)72-39(23-97-96-20-32(60)48(83)70-38)53(88)67-35(18-43(61)78)58(93)74-15-3-4-42(74)56(91)63-26)24-100-98-21-37(64-44(79)19-62-57(92)46(27(2)75)73-55(41)90)51(86)68-36(59(94)95)17-29-7-11-31(77)12-8-29/h5-12,26-27,32-42,46,75-77H,3-4,13-25,60H2,1-2H3,(H2,61,78)(H,62,92)(H,63,91)(H,64,79)(H,65,87)(H,66,84)(H,67,88)(H,68,86)(H,69,82)(H,70,83)(H,71,85)(H,72,89)(H,73,90)(H,80,81)(H,94,95)/t26-,27+,32-,33-,34-,35-,36-,37-,38-,39-,40-,41-,42-,46-/m0/s1 N
  • Key:KXGCNMMJRFDFNR-WDRJZQOASA-N N
 NYesY (what is this?)  (verify)

Linaclotide (marketed under the trade name Linzess and Constella) is a peptide agonist of guanylate cyclase 2C. It was approved by the FDA in August 2012 for the treatment of chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) in adults.[1]

Background

The National Institutes of Health (NIH) estimate 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.[2]

Linaclotide is a peptide agonist which mimics the action of endogenous guanylin and uroguanylin, both of which activate the cell surface receptor of guanylate cyclase 2C (GC-C).[3]:108–109[4] The medication binds to the surface of the intestinal epithelial cells.[4] Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses.[3]:108 Activation of GC-C increases cyclic guanosine monophosphate (cGMP).[4] 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.[4][5] This results in increased intestinal fluid and accelerated transit.[4] By elevating cGMP, linaclotide is also considered to reduce activation of colonic sensory neurons, reducing pain;[4] and activates colonic motor neurons, which increases smooth muscle contraction and thus promotes bowel movements.

Clinical trials

The approved dose for constipation-predominant irritable bowel syndrome IBS-C is 290 micrograms daily; the approved dose for chronic idiopathic constipation CIC is 145 mcg daily.[1] The package insert contains the details of the medications response rates and side effects.[4]

42 patients with chronic constipation participated in a pilot randomized, double-blind, placebo-controlled study; improved bowel habits and overall symptoms were observed.[6] The FDA approval of linaclotide was based on 4 larger randomized trials, 2 for each indication: IBS-C and CIC.[4] In a Phase III clinical trial announced in September 2010, 800 patients were given linaclotide or a placebo for 12 weeks 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.[2]

Distribution and licensing

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.[7] Distribution rights in the United States will be shared with Forest Laboratories, with Almirall distributing linaclotide in Europe and Astellas Pharma in Asia.[2]

Chemistry

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

H–Cys1–Cys2–Glu3–Tyr4–Cys5–Cys6–Asn7–Pro8–Ala9–Cys10–Thr11–Gly12–Cys13–Tyr14–OH

There are three disulfide bonds: Between Cys1 and Cys6, between Cys2 and Cys10, and between Cys5 and Cys13.[8]

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References

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External links

  1. ↑ 1.0 1.1 "FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation" Food and Drug Administration news release, August 30, 2012. Accessed April 28, 2016.
  2. ↑ 2.0 2.1 2.2 Pollack, Andrew. "Drug for Irritable Bowel Achieves Goals in Trial", The New York Times, September 13, 2010. Accessed September 14, 2010.
  3. ↑ 3.0 3.1 Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Linzess package insert, Allergan, Plc, revised November 2015. Accessed April 28, 2016.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Johnston, Jeffrey M; Kurtz, Caroline B.; Drossman, Douglas A.; et al. "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.
  7. ↑ Staff. "Daily International Pharma Alert", FDANews, September 17, 2007, Vol. 4 No. 182. Accessed September 15, 2010.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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