Teduglutide Chemical Properties

solubility 

Methanol (Slightly), Water (Slightly)

form 

Solid

color 

White to Off-White

Stability:

Hygroscopic

InChIKey

CILIXQOJUNDIDU-ASQIGDHWSA-N

Safety Information

WGK Germany 

WGK 3

Storage Class

11 - Combustible Solids

Hazardous Substances Data

197922-42-2(Hazardous Substances Data)

Teduglutide Usage And Synthesis

Description

Teduglutide was approved in August 2012 by the European Commission and in December 2012 by the US FDA for the treatment of adults with short bowel syndrome (SBS) who are dependent on parenteral nutrition (PN). Teduglutide (also known as ALX-0600) is a GLP-2 analogue in which glycine has been substituted for alanine at position 2 from the N-terminus, thereby conferring resistance to degradation by DPP-4. Teduglutide has similar binding affinity, agonist potency, and agonist efficacy as GLP-2 in assays with the rat GLP-2 receptor. Administration of teduglutide to rats gave a significant increase in small intestine weight and an increase in the height of intestinal villi. Teduglutide was prepared by solid-phase peptide synthesis.

Originator

NPS Allelix (Canada)

Uses

Treatment of intestinal diseases characterized by chemical or surgical damage of the intestinal epithelium such as Short Bowel Syndrome (SBS) or damage to the intestinal epithelium due to disease (glucagon-like peptide-2 (GLP- 2) analog).

Definition

ChEBI: A 33-membered polypeptide consisting of His, Gly, Asp, Gly, Ser, Phe, Ser, Asp, Glu, Met, Asn, Thr, Ile, Leu, Asp, Asn, Leu, Ala, Ala, Arg, Asp, Phe, Ile, Asn, Trp, Leu, Ile, Gln, Thr, Lys, Ile, Thr and Asp residues joined in sequence. A glucagon-like pep ide-2 receptor agonist used for the treatment of short-bowel syndrome.

Application

Teduglutide is a peptide hormone that is used to treat pediatric patients with long-term efficacy. It has been shown to be effective in the treatment of autoimmune diseases and bowel disease. It is a long-acting analogue of glucagon-like peptide 1 (GLP-1). The drug has been shown to have high chemical stability, which means it does not break down easily. Teduglutide is injected into the body and taken up by cells, where it activates receptors on the surface of cells. This activation leads to increased glucose production by the liver and improved insulin sensitivity in peripheral tissues such as muscle, fat, and liver. It also increases heart rate and blood pressure.

brand name

Gattex

Mechanism of action

Gattex (teduglutide) is an analog of naturally occurring human glucagon-like peptide 2 (GLP-2), a peptide secreted primarily in the distal intestine and involved in the regeneration and repair of the intestinal epithelium. GLP-2 is known to increase intestinal and portal blood flow, and inhibit gastric acid secretion.Teduglutide binds to the GLP-2 receptors located in intestinal subpopulations of enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus. Activation of these receptors results in the local release of multiple mediators including insulin-like growth factor (IGF)-1, nitric oxide and keratinocyte growth factor (KGF).

Clinical Use

Human glucagon-like peptide-2 (GLP-2):
Treatment of short bowel syndrome

Side effects

Side effects that you should report to your care team as soon as possible:
Allergic reactions—skin rash, itching, hives, swelling of the face, lips, tongue, or throat
Bowel blockage—stomach cramping, unable to have a bowel movement or pass gas, loss of appetite, vomiting
Gallbladder problems—severe stomach pain, nausea, vomiting, fever
Pancreatitis—severe stomach pain that spreads to your back or gets worse after eating or when touched, fever, nausea, vomiting

Synthesis

Teduglutide is synthesized by two main methods, sequential coupling and fragment coupling, in which sequential coupling is a pure solid-phase sequential coupling method for peptide synthesis using wang resin as a carrier, and the final cleavage of tidurutide is obtained. The formation of the five-membered ring structure has a significant relationship with the right amino acid of Asp or Asn, while Gly is most likely to form a ring structure when Gly is coupled before Asp due to the absence of a protecting group in the side chain and the small spatial site resistance. Therefore, the use of sequential coupling will inevitably lead to the formation of a five-membered ring during the synthesis of the N-terminal 3rd to 4th amino acids of teduglutide, which will result in the reduction of purity. Therefore, in order to solve the problem of degradation of the Asp-Gly fragment, the fragment coupling was used to first synthesize a fully protected fragment with the structure shown in SEQ ID NO:2, which is the N-terminal 1st to 4th amino acids of teduglutide, including the Asp-Gly structure, and then purify the fully protected fragment and use the purified Then the fully protected fragment was purified, and the purified fully protected fragment was solid-phase coupled with a fragmented peptide resin having the structure shown in SEQ ID NO:12, and finally tidurutide was obtained by cleavage.

Drug interactions

Potentially hazardous interactions with other drugs
Potential for increased absorption of some medications. Monitor narrow therapeutic index drugs carefully.

Metabolism

The metabolism of teduglutide is not fully known. Since teduglutide is a peptide it is likely that it follows the principal mechanism for peptide metabolism. See 'Other information'.

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