Saxagliptin 361442-04-8
Saxagliptin , previously identified as BMS-477118, is a new oral hypoglycemic of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug. A New Drug Application for saxagliptin in the treatment of type 2 diabetes was submitted to the FDA in June 2008. It was based on a drug development program with 8 randomized trials: 1 phase 2 dose-ranging (2. 5–100 mg/d) study; 6 phase 3, 24-week controlled trials with additional controlled follow-up from 12 to 42 months, double-blinded throughout; and one 12-week mechanism-of-action trial with a 2-year follow-up period. In June 2008, it was announced that Onglyza would be the trade name under which saxagliptin will be marketed. The FDA approved Onglyza on July 31, 2009. Dipeptidyl peptidase-4's role in blood glucose regulation is thought to be through degradation of GIP and the degradation of GLP-1. Bristol-Myers Squibb announced on 27 December 2006 that Otsuka Pharmaceutical Co. has been granted exclusive rights to develop and commercialize the compound in Japan. Under the licensing agreement, Otsuka will be responsible for all development costs, but Bristol-Myers Squibb retains rights to co-promote saxagliptin with Otsuka in Japan. Further, on 11 January 2007 it was announced that Bristol-Myers Squibb and AstraZeneca would work together to complete development of the drug and in subsequent marketing.
Production
Saxagliptin is produced industrially by Bristol-Myers Squibb by the amide coupling of N-Boc-3-hydroxyadamantylglycine (2) and methanoprolineamide (3) with EDC. The former is commercially available, whereas the latter is available as the N-Boc analog. The prolineamide moiety is subsequently dehydrated with trifluoroacetic anhydride to give the cyanide as the trifluoracetate ester, which is hydrolyzed. Removal of the Boc protecting group, followed by neutralization gives the desired product (1)::450px
How saxagliptin works
Onglyza is part of a class of diabetes medications called dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 is an enzyme that breaks down incretin hormones. As a DPP-4 inhibitor, Onglyza slows down the breakdown of incretin hormones, increasing the level of these hormones in the body. It is this increase in incretin hormones that is responsible for the beneficial actions of Onglyza, including increasing insulin production in response to meals and decreasing the amount of glucose (sugar) that the liver produces. Because incretin hormones are more active in response to higher blood sugar levels (and are less active in response to low blood sugar), the risk of dangerously low blood sugar (hypoglycemia) is low with Onglyza.
Efficacy
Oral saxagliptin 2. 5 or 5 mg once daily suppresses DPP4 activity for 24 hours, significantly improving mean HbA1c levels (relative to placebo) in well designed, 24-week trials in treatment-naive patients with type 2 diabetes. Combination therapy with saxagliptin 5 mg once daily and metformin was more effective than saxagliptin or metformin monotherapy.
Tolerability
Both monotherapy and combination therapy with other agents was generally well tolerated in clinical trials. . A study of DPP-4 inhibition in human non-small cell lung cancer (NSCLC) concluded that "DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells. The risk of cancer suppression with DPP-4 down-regulation applies to all the DPP-4 inhibitors on the market in addition to saxagliptin (sitagliptin and vildagliptin)
| Systematic (IUPAC) name: | (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile |
|---|---|
| Saxagliptin CAS number: | 361442-04-8 |
| ATC code: | A10BH03 |
| PubChem: | 11243969 |
| DrugBank: | DB06335 |
| Formula: | C18H25N3O2 |
| Molecular mass: | 315.41 g/mol |
| Saxagliptin Assay/Purity: | Typically NLT 98% |
