saxagliptin

saxagliptin
IUPAC name	(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile
Tradename	Onglyza, others
Drugs.com	Monograph
MedlinePlus	a610023
Pregnancy AU	B3
Routes of administration	By mouth
Bioavailability	75%
Protein bound	Negligible
Metabolism	CYP3A4/CYP3A5-mediated to active metabolite
Elimination half-life	2.5 hours (parent), 3.1 hours (metabolite)
Excretion	Urine (75%, 24% as metabolite), feces (22%)
CAS number	361442-04-8
PubChem	11243969
ChemSpider	9418967
UNII	J70MA6E1X9
KEGG	D08875
ChEBI	63637
ChEMBL	1242205
Chemical formula	C18H25N3O2
Molecular weight	315.417 g/mol

saxagliptin is an oral antidiabetic medication belonging to the dipeptidyl peptidase-4 inhibitor class, used for the treatment of type 2 diabetes mellitus. It is typically prescribed as an adjunct to diet and exercise, and is often used in combination with other agents like metformin, a sulfonylurea, or a thiazolidinedione. The drug works by inhibiting the enzyme dipeptidyl peptidase-4, thereby increasing levels of active incretin hormones which stimulate insulin secretion and suppress glucagon release.

Medical uses

Saxagliptin is indicated as a monotherapy or in combination with other antihyperglycemic agents to improve glycemic control in adults with type 2 diabetes mellitus. It is frequently combined with foundational therapies like metformin or sulfonylurea drugs such as glipizide when adequate control is not achieved with a single agent. Clinical trials, including the SAVOR-TIMI 53 trial, have demonstrated its efficacy in reducing hemoglobin A1c levels. It is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Adverse effects

Common adverse effects include upper respiratory tract infection, urinary tract infection, and headache. More serious concerns identified in post-marketing studies involve an increased risk of hospitalization for heart failure, as highlighted by the U.S. Food and Drug Administration and data from the SAVOR-TIMI 53 study. Other potential severe effects include acute pancreatitis, severe joint pain, and bullous pemphigoid. Hypersensitivity reactions such as angioedema and anaphylaxis have been reported.

Pharmacology

Saxagliptin is a potent, selective, and reversible inhibitor of the enzyme dipeptidyl peptidase-4. By inhibiting this enzyme, it prolongs the activity of endogenous incretin hormones, primarily glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. This mechanism enhances glucose-dependent insulin secretion from pancreatic beta cells and suppresses elevated glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. Its active metabolite, 5-hydroxy saxagliptin, possesses half the potency of the parent compound.

Chemistry

Saxagliptin is chemically described as (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile. It is a small molecule drug featuring an adamantane derivative moiety and a cyanopyrrolidine structure, which is characteristic of many dipeptidyl peptidase-4 inhibitors. The compound exists as a white to light-colored powder and is formulated as the hydrochloride salt for pharmaceutical use, marketed under the brand name Onglyza by Bristol-Myers Squibb and AstraZeneca.

History

Saxagliptin was discovered and developed through a collaboration between Bristol-Myers Squibb and Otsuka Pharmaceutical. It received its initial approval from the U.S. Food and Drug Administration in July 2009, following review of clinical data submitted by the sponsors. The European Medicines Agency granted marketing authorization in the European Union later that same year. Its development was part of a broader pharmaceutical industry effort to target the incretin system for diabetes management following the success of sitagliptin.

Society and culture

Saxagliptin is marketed under the trade name Onglyza in many countries, including the United States and members of the European Union. It has been the subject of significant post-marketing safety reviews by regulatory bodies like the U.S. Food and Drug Administration and the European Medicines Agency, particularly regarding cardiovascular risks. The drug is available as a generic medication in several markets following patent expirations. It is listed on the World Health Organization Model List of Essential Medicines.

Category:Dipeptidyl peptidase-4 inhibitors Category:Anti-diabetic drugs Category:AstraZeneca