Linaclotide, (sold under the brand name Linzess in the US and Mexico, and as Constella elsewhere) is a drug used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause. It has a black box warning about the risk of serious dehydration in children in the US; the most common adverse effects in others are gastrointestinal.It is an oligo-peptide agonist of guanylate cyclase 2C and remains in the GI tract after it is taken orally. It was approved in the US and Europe in 2012.It is marketed by Allergan in most of the world and by Astellas in Asia; Ironwood Pharmaceuticals was the originator. In 2017, it was the 257th most commonly prescribed medication in the United States, with more than one million prescriptions. Medical use
Linaclotide is used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause.It has not been tested in pregnant women and it is unknown if it is excreted in breast milk. Adverse 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.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.
It is a synthetic tetradecapeptide (14 amino acid peptide) with the sequence CCEYCCNPACTGCY by one-letter abbreviation, or by three-letter abbreviation:H–Cys1–Cys2–Glu3–Tyr4–Cys5–Cys6–Asn7–Pro8–Ala9–Cys10–Thr11–Gly12–Cys13–Tyr14–OH
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; 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:

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. History
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 labs know-how and inventions related to microbial pathogens and biology. In 2002 the company hired Mark Currie who had worked at the Searle division of Monsanto and then had gone to Sepracor. 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 travelers diarrhea.