910463-68-2

Semaglutide, sold under the brand name Ozempic among others, is an anti-diabetic medication used for the treatment of type 2 diabetes and chronic weight management. Semaglutide acts like human glucagon-like peptide-1 (GLP-1) such that it increases insulin secretion, thereby increasing sugar metabolism. It is distributed as a metered subcutaneous injection in a prefilled pen, or as an oral form. One of its advantages over other antidiabetic drugs is that it has a long duration of action, thus, only once-a-week injection is sufficient.

The story of semaglutide began in the 1980s when scientists (such as Joel Habener and Jens Juul Holst) discovered GLP-1, a hormone in the human body that regulates blood sugar and appetite. However, its highly degradable nature limited its potential for medicinal use. In the 1990s, researchers at Novo Nordisk in Denmark, including Lotte Bjerre Knudsen, drew inspiration from the Gila monster's venom protein Exendin-4 and successfully developed the first GLP-1 drug, exenatide. In pursuit of a longer-acting drug, the Novo Nordisk team, led by Knudsen, created a once-daily liraglutide in the 2000s by structurally modifying human GLP-1 and adding fatty acid chains. Building on this success, the team further optimized the formula, ultimately leading to the development of semaglutide, with a longer half-life, by scientists including a research team led by Mads Krogsgaard Thomsen. It was approved in 2017 as a once-weekly blood sugar lowering drug (Ozempic), and in 2021 it shocked the world with its remarkable effects in the field of weight loss (Wegovy), evolving from a scientific concept into a benchmark drug that changes the treatment of metabolic diseases.

Semaglutide(910463-68-2) is used to manage type 2 diabetes along with lifestyle changes, such as dietary restrictions and increased physical activity. It also works by slowing the movement of food through the stomach and may decrease appetite and cause weight loss. There have been no published reports of hepatotoxicity attributed to semaglutide therapy.

ChEBI: Semaglutide is a polypeptide that contains a linear sequence of 31 amino acids joined together by peptide linkages. It is an agonist of glucagon-like peptide-1 receptors (GLP-1 AR) and used for the treatment of type 2 diabetes. It has a role as a hypoglycemic agent, a glucagon-like peptide-1 receptor agonist, an anti-obesity agent, a neuroprotective agent and an appetite depressant. It is a polypeptide and a lipopeptide.

Semaglutide (Rybelsus, Ozempic, NN9535, OG217SC, NNC 0113-0217), a long-acting glucagon-like peptide 1 (GLP-1) analogue, is a GLP-1 receptor agonist with the potential for the treatment of type 2 diabetes mellitus (T2DM).

Semaglutide is a glucagon-like peptide-1 receptor agonist. It increases the production of insulin, a hormone that lowers the blood sugar level. It also appears to enhance growth of β cells in the pancreas, which are the sites of insulin production. It also inhibits glucagon, which is a hormone that increases blood sugar. It additionally reduces food intake by lowering appetite and slows down digestion in the stomach. In this way it reduces body fat.

Median t_{max,semaglutide} was 1.5 hours for both water volumes with a range of 0.5-3.0 hours for 50 mL and a range of 0.5-4.0 hours for 240 mL. AUC_0-24h,_semaglutide and C_{max,semaglutide} were approximately 70% higher when dosed with 50 versus 240 mL water[2].

Side effects including nausea, vomiting, diarrhea, abdominal pain, and constipation may occur. In people with heart problems, it can cause damage to the back of the eye (retinopathy). Side effects include kidney problems, diabetic retinopathy, allergic reactions, low blood sugar, and pancreatitis.

Semaglutide is synthesized from two intermediate compounds by chemical reaction, with the specific steps as follows:
(1) Preparation of Compound 2: Starting from Arg34GLP-1(9-37), side-chain modifications are performed on Arg34GLP-1(9-37) and the 26-Lys residue of Compound 1. An acyl coupling reaction is conducted under specific reaction pH conditions. The solid is obtained after post-treatment, and the reaction mixture is adjusted to its isoelectric point for precipitation to yield Compound 2;
(2) Preparation of Compound 4: Compound 3 was activated. Under the action of a condensing reagent and base, an acyl-coupling reaction was performed on the terminal amino group of Arg34GLP-1(9-37) in the activated compound 2 to yield Compound 4;
(3) Preparation of Semaglutide: Using Compound 4 as the starting material, deprotection was carried out in a cleavage solution to obtain Semaglutide.

Semaglutide is selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib8, Arg34) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) is three-fold decreased compared to liraglutide, whereas the albumin affinity is increased.

The plasma half-life is 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs.

Intact semaglutide was the primary component circulating in plasma for humans and both nonclinical species, accounting for 69–83% of the total amount of semaglutide-related material, and was metabolised prior to excretion. Recovery of excreted radioactivity was 75.1% in humans, 72.1% in rats and 58.2% in monkeys. Urine and faeces were shown to be important routes of excretion, with urine as the primary route in both humans and animals[1]. Semaglutide was metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain, and metabolism was not confined to specific organs. Intact semaglutide in urine accounted for 3.1% of the administered dose in humans and less than 1% in rats; it was not detected in urine in monkeys.

The FDA recommends Wegovy for weight loss if you meet one of the following criteria: Have a body mass index (BMI) of 27kg/m2 or greater and at least one weight-related condition, such as high blood pressure, Type 2 diabetes, or high cholesterol; Have a BMI of 30kg/m2 or greater.
Avoid semaglutide if you have: History of medullary thyroid cancer; History of gallbladder disease; History of pancreatitis; Multiple endocrine neoplasia syndrome type 2 (MEN2).

[1] A, Lene Jensen , et al. "Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species." European Journal of Pharmaceutical Sciences 104(2017):31-41.
[2] Tine A. B?kdal. “Relationship Between Oral Semaglutide Tablet Erosion and Pharmacokinetics: A Pharmacoscintigraphic Study.” Clinical Pharmacology in Drug Development 10 5 (2021): 453–462.