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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).
Trade namesLinzess, Constella
  • 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
Drug classGuanylate cyclase-C (GC-C) agonist[2]
Main usesIBS-C, chronic constipation of unknown cause[2]
Side effectsDiarrhea, abdominal pain, intestinal gas[3][4]
  • US: N (Not classified yet)
Routes of
By mouth
Typical dose72 to 290 mcg OD[4]
External links
License data
Legal status
Chemical and physical data
Molar mass1526.73 g·mol−1
3D model (JSmol)
  • 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

Linaclotide, sold under the brand name Linzess and Constella, is a medication used to treat irritable bowel syndrome with constipation and chronic constipation of unknown cause.[2] It is taken by mouth.[2]

Common side effects include diarrhea, abdominal pain, and intestinal gas.[3][4] Rarely this may lead to dehydration, low potassium, and low blood pressure with standing.[3] It works by attaching to guanylate cyclase C receptors in the intestines which results in greater fluid release.[3]

Linaclotide was approved for medical use in the United States and Europe in 2012.[3][2] In 2017, it was the 257th most commonly prescribed medication in the United States, with more than one million prescriptions.[5][6] In the United Kingdom 4 weeks of medication costs the NHS about £38 as of 2021.[7] This amount in the United States costs about 430 USD.[8]

Medical use

Linaclotide is used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause.[9][10]

It has not been tested in pregnant women and it is unknown if it is excreted in breast milk.[10]


It is taken at a dose of 290 mcg per day for IBS and 72 to 145 mcg for constipation of unknown cause.[4]

Side effects

The US label has a black box warning to not use linaclotide in children less than 6 years old and to avoid in people from 6 to 18 years old, due to the risk of serious dehydration.[9]

More than 10% of people taking linaclotide have diarrhea. Between 1% and 10% of people have decreased appetite, dehydration, low potassium, dizziness when standing up too quickly, nausea, vomiting, urgent need to defecate, fecal incontinence, and bleeding in their colon, rectum, and anus.[10]


Systemic absorption of the globular tetradecapeptide is minimal.[11][12]

Linaclotide, like the endogenous guanylin and uroguanylin it mimics, is an agonist that activates the cell surface receptor of guanylate cyclase 2C (GC-C).[11][13][14] The medication binds to the surface of the intestinal epithelial cells.[13] Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses.[11] Activation of GC-C increases cyclic guanosine monophosphate (cGMP).[13] 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.[13][15] This results in increased intestinal fluid and accelerated transit.[13] By elevating cGMP, linaclotide is also considered to reduce activation of colonic sensory neurons, reducing pain;[13][12] and activates colonic motor neurons, which increases smooth muscle contraction and thus promotes bowel movements.[citation needed]


Linaclotide is a peptide mimic of endogenous guanylin and uroguanylin.[11][14] It is a synthetic tetradecapeptide (14 amino acid peptide) with the sequence CCEYCCNPACTGCY by one-letter abbreviation,[citation needed] or by three-letter abbreviation:[16]


However, the actual structure of linaclotide is not fully 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;[16] 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]

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-butylsulphenyl 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.[16]


The drug was discovered at Microbia, Inc, which had been spun out of the Whitehead Institute in 1998 by postdocs from the lab of Gerald Fink to commercialize the lab's know-how and inventions related to microbial pathogens and biology.[17][18] In 2002 the company hired Mark Currie who had worked at the Searle division of Monsanto and then had gone to Sepracor.[17] Currie directed the efforts that led to the discovery of linaclotide, which was based on an enterotoxin produced by some strains of Escherichia coli that cause traveler’s diarrhea.[19][20] The company started Phase I trials in 2004.[17]

Under a partnership agreement announced in 2007 between Forest Laboratories and Microbia, Forest would pay $70 million in licensing fees towards the development of linaclotide, with profits shared between the two companies in the US; Forest obtained exclusive rights to market in Canada and Mexico.[21] By 2010, Microbia had changed its name to Ironwood Pharmaceuticals and had licensed rights to distribute the drug in Europe to Almirall and had licensed Asian rights to Astellas Pharma.[22]

It was approved in the US and Europe in 2012.[23]

Forest was acquired in 2014 and eventually became part of Allergan.[24] Allergan acquired rights from Almirall in 2015[25] and in 2017 acquired remaining rights in most of the rest of the world, excluding North America, Japan, and China.[26]

In 2014, Ironwood and Forest then Allergan began running direct-to-consumer advertising which raised sales by 21%; campaigns in 2015 and 2016 raised sales by 27% and 30%.[27]

In January 2017, plecanatide, a drug marketed under the name Trulance, was approved by the FDA for the treatment of chronic idiopathic constipation (CIC), and is likewise an agonist of guanylate cyclase, except with hexadecapeptide structure.[28]

It is marketed by Allergan in most of the world and by Astellas in Asia; Ironwood Pharmaceuticals was the originator.[29]

Society and culture


In 2017, the list price for linaclotide in the US was $378 for 30 pills and plecanatide was priced the same; Allergan and Ironwood increased the price of linaclotide to around $414 in 2018.[29]

The medication in the U.S. is at a cost of $497 (USD) for 30 capsules, 72 mcg[30] In 2017, it was the 257th most commonly prescribed medication in the United States, with more than one million prescriptions.[5][6]


  1. Oh, See Arr (August 17, 2011). "Macrocycle Milestone for Ironwood Pharma". The Haystack. Archived from the original on 5 June 2019. Retrieved 11 February 2017 – via
  2. 2.0 2.1 2.2 2.3 2.4 "Linaclotide Monograph for Professionals". Archived from the original on 19 October 2021. Retrieved 23 November 2021.
  3. 3.0 3.1 3.2 3.3 3.4 "Constella". Archived from the original on 22 June 2021. Retrieved 23 November 2021.
  4. 4.0 4.1 4.2 4.3 "DailyMed - LINZESS- linaclotide capsule, gelatin coated". Archived from the original on 29 March 2021. Retrieved 23 November 2021.
  5. 5.0 5.1 "The Top 300 of 2020". ClinCalc. Archived from the original on 12 February 2021. Retrieved 11 April 2020.
  6. 6.0 6.1 "Linaclotide - Drug Usage Statistics". ClinCalc. Archived from the original on 8 July 2020. Retrieved 11 April 2020.
  7. BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 52. ISBN 978-0857114105.
  8. "Linaclotide Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 23 November 2021.
  9. 9.0 9.1 "US label for linaclotide" (PDF). FDA. January 2017. Archived (PDF) from the original on 20 March 2021. Retrieved 15 April 2018. For label updates see FDA index page for NDA 202811 Archived 2017-06-28 at the Wayback Machine
  10. 10.0 10.1 10.2 "UK label: Linaclotide Summary of Product Characteristics". Electronic Medicines Compendium. September 2017. Archived from the original on 15 April 2018. Retrieved 15 April 2018.
  11. 11.0 11.1 11.2 11.3 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 4836568. PMID 27099579.
  12. 12.0 12.1 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 4040778. PMID 24917937.{{cite journal}}: CS1 maint: uses authors parameter (link)
  13. 13.0 13.1 13.2 13.3 13.4 13.5 Linzess package insert Archived 2016-05-10 at the Wayback Machine, Allergan, plc, revised November 2015. Accessed August 18, 2016.
  14. 14.0 14.1 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.
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  16. 16.0 16.1 16.2 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. 96 (1): 69–80. doi:10.1002/bip.21480. PMID 20560145. S2CID 46150263. Archived from the original (PDF) on February 11, 2017. Retrieved February 10, 2017.{{cite journal}}: CS1 maint: uses authors parameter (link)
  17. 17.0 17.1 17.2 Withers, Melissa (September 22, 2004). "Druhunters". Paradigm Magazine, Whitehead Institute. Archived from the original on August 28, 2021. Retrieved April 15, 2018.
  18. Timmerman, Luke (23 February 2009). "Xconomy: Renewables Aren't Just for Biofuels: Microbia Makes Industrial Chemicals a Bit Greener". Xconomy. Archived from the original on 16 April 2018. Retrieved 15 April 2018.
  19. Hornby, PJ (2015). "Drug discovery approaches to irritable bowel syndrome". Expert Opinion on Drug Discovery. 10 (8): 809–24. doi:10.1517/17460441.2015.1049528. PMID 26193876. S2CID 207494271.
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External links