851199-59-2

Basic information

• Product Name: Linaclotide
• Synonyms: Linaclotide;Linaelotide Acetate;Linaelotide
• CAS NO: 851199-59-2
• Molecular Formula: C59H79N15O21S6
• Molecular Weight: 1526.73646
• Product Categories: Inhibitors
• Mol File: 851199-59-2.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 2045.0±65.0 °C(Predicted)
• Appearance: /
• Density: 1.60
• Storage Temp.: Hygroscopic, Refrigerator, under inert atmosphere
• Solubility: DMSO (Slightly, Heated), Methanol ((Slightly, Heated)), Water (Slightly, Heated)
• PKA: 3.05±0.10(Predicted)
• CAS DataBase Reference: Linaclotide(CAS DataBase Reference)
• NIST Chemistry Reference: Linaclotide(851199-59-2)
• EPA Substance Registry System: Linaclotide(851199-59-2)

Safety Data

• Hazardous Substances Data: 851199-59-2(Hazardous Substances Data)

Usage

Description

In August 2012, the US FDA approved linaclotide (also referred to as MD-1100), a first-in-class, orally administered 14-amino acid peptide as a therapy for patients suffering from chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Linaclotide and its active metabolite MM-419447, which results from the cleavage of the C-terminal tyrosine residue by carboxypeptidase A, mimic the actions of the endogenous intestinal peptides guanylin (15 amino acids) and uroguanylin (16 amino acids) by activating guanylyl cyclase C (GC-C) on the intestinal epithelium. Activation of GC-C leads to increased intra- and extracellular levels of cGMP and activation of the CFTR ion channel, resulting in increased levels of HCO3-, Cl-, and water in the intestinal lumen and accelerated gastrointestinal transit. Based on an in vitro assaymeasuring the accumulation of cGMP in T84 cell exposed to an agonist, the EC50 of linaclotide at pH 7.0 was 99±17.5 nM. In preclinical studies in mice using the transit of activated charcoal as ameasure of efficacy, linaclotide at 100 μg/kg significantly accelerated transit compared to wild-type mice treated with charcoal only or GC-Cnullmice treatedwith and without linaclotide.118 Efficacy was also seen in rats treatedwith linaclotide atdoses of 5, 10, and 20 μg/kg. Linaclotide has been synthesized using conventional solid-phase peptide technology.

Originator

Ironwood Pharmaceuticals and Forest Pharmaceuticals (United States)

Uses

Linaclotide is a guanylate cyclase-C agonist currently being studied in Phase 3 trials for the treatment of irritable bowel syndrome with constipation.

Brand name

Linzess

Relevant articles and documents

Chemical synthesis and structural analysis of guanylate cyclase C agonist linaclotide

Guanylate cyclase C (GC-C) is an important receptor protein expressed by intestinal epithelial cells, and its dysregulation leads to severe intestinal diseases. Linaclotide is a 14-amino acid peptide approved by the FDA for the treatment of irritable bowel syndrome with constipation (IBS-C), which activates guanylate cyclase C to accelerate intestinal transit. Drug molecule design based on structural information plays a crucial role and the activity of linaclotide still need to improve, while the structure of linaclotide remains unknown. In this work, linaclotide and its D-enantiomer were obtained through Fmoc solid phase peptide synthesis method and co-crystalized through racemic crystallization. The crystal structure showed that linaclotide has a tight, three-beta turns structure immobilized by three pairs of disulfide bonds.