Saxagliptin

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Saxagliptin
Saxagliptin.svg
Systematic (IUPAC) name
(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)
acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile
Clinical data
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a610003
Licence data EMA:Link, US FDA:link
Legal status POM (UK) -only (US)
Routes Oral
Identifiers
CAS number 361442-04-8 N
ATC code A10BH03
PubChem CID 11243969
DrugBank DB06335
ChemSpider 9419005 YesY
UNII 8I7IO46IVQ N
ChEMBL CHEMBL385517 YesY
Chemical data
Formula C18H25N3O2 
Mol. mass 315.41 g/mol
 N (what is this?)  (verify)

Saxagliptin (rINN), previously identified as BMS-477118, is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.1 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. In June 2008, it was announced that Onglyza would be the trade name under which saxagliptin will be marketed.2

While used for type 2 diabetes the evidence does not show a change in hard end points such as the risk of heart attacks or strokes.3

Medical uses

Saxagliptin is used as monotherapy or in combination with other drugs for the treatment of Type 2 diabetes. It does not appear to decrease the risk of heart attacks or strokes.3 It increases the risk of hospitalization for heart failure by about 27%. Like other DPP-4 inhibitors, it has relatively modest HbA1c lowering ability, is associated with a relatively modest risk of hypoglycemia, and does not cause weight gain.34

Saxagliptin improved mean HbA1c levels (relative to placebo) in a 24-week trial in people with type 2 diabetes.5 Combination therapy with saxagliptin and metformin was more effective than saxagliptin or metformin monotherapy.5 When the relative benefits of increasing the dose of a sulfonylurea or adding saxagliptin were assessed in a study of 768 patients, combination treatments were shown to have a significantly greater impact on fasting blood glucose than increasing the tested glibenclamide dose alone.6

Adverse effects

In 4148 patients studied, 3 adverse reactions were seen higher in saxaglyptin vs placebo. Table 1: Adverse Reactions (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Trials* Reported in ≥ 5% of Patients Treated with ONGLYZA (saxagliptin tablets) 5 mg and More Commonly than in Patients Treated with Placebo.7

Number (%) of Patients
ONGLYZA 5 mg N=882 Placebo N=799
Upper respiratory tract infection 68 (7.7) 61 (7.6)
Urinary tract infection 60 (6.8) 49 (6.1)
Headache 57 (6.5) 47 (5.9)7
  • The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue.7

In February 2012, Bristol-Myers/Astra Zeneca distributed additional safety information on saxagliptin use in South Africa. The package insert is to be edited for South Africa. Contraindications will now include a history of sensitivity to saxagliptin (or another DPP4 inhibitor) as well as pancreatitis. Spontaneously-reported adverse events in South Africa have included anaphylaxis, angioedema and acute pancreatitis.

In a cardiovascular outcomes trial, saxagliptin treatment let to a small but statistically significant increase in the risk of being hospitalized for heart failure. 3

Tolerability

Both monotherapy and combination therapy with other agents was generally well tolerated in clinical trials.5

Possible association with pancreatitis and pancreatic cancer

An association of the DPP-IV inhibitor class with pancreatic problems has been proposed, mainly based on case reports associated with the DPP-IV inhibitor sitagliptin and several incretin mimetics including exanatide. A 2013 study of the DPP-4 inhibitor sitagliptin reported found "worrisome changes in the pancreases of the rats that could lead to pancreatic cancer".8 A second paper by the same authors reported an increase in precancerous lesions in the pancreases of organ donors who had taken GLP-1 inhibitors.9 In response to these reports, the United States FDA and the European Medicines Agency each undertook independent reviews of all clinical and preclinical data related to the possible association of DPP-IV inhibitors with pancreatic cancer. In a joint letter to the New England Journal of Medicines, the agencies stated that "Both agencies agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data. The FDA and the EMA have not reached a final conclusion at this time regarding such a causal relationship. Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal."10

Lawsuits have been filed in which plantiffs who developed pancreatic cancer claim that DPP-IV inhibitors or incretins had a causative role in the development of their cancers.1112

Production

The synthesis of Saxagliptin 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):13

Production of saxagliptin.png

Pharmacology

Saxagliptin 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, Saxagliptin 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 Saxagliptin, including increasing insulin production in response to meals and decreasing the rate of gluconeogenesis in the liver.14

Dipeptidyl peptidase-4's role in blood glucose regulation is thought to be through degradation of GIP15 and the degradation of GLP-1.1516

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 Saxagliptin.

Licensing

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.17 The FDA approved Saxagliptin with brand name Onglyza on July 31, 2009.18

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.19 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.20

See also

References

  1. ^ Augeri D et al. (2005). "Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes". Journal of Medicinal Chemistry 48 (15): 5025–5037. doi:10.1021/jm050261p. PMID 16033281. 
  2. ^ "Bristol, Takeda Drugs Offer Alternatives to Januvia (Update2)". Bloomberg. 2008-06-07. 
  3. ^ a b c d Scirica, BM; Bhatt, DL; Braunwald, E; Steg, PG; Davidson, J; Hirshberg, B; Ohman, P; Frederich, R; Wiviott, SD; Hoffman, EB; Cavender, MA; Udell, JA; Desai, NR; Mosenzon, O; McGuire, DK; Ray, KK; Leiter, LA; Raz, I; the SAVOR-TIMI 53 Steering Committee and, Investigators (Oct 3, 2013). "Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus.". The New England journal of medicine 369 (14): 1317–1326. PMID 23992601. 
  4. ^ Ali S, Fonseca V (January 2013). "Saxagliptin overview: special focus on safety and adverse effects". Expert Opin Drug Saf 12 (1): 103–9. doi:10.1517/14740338.2013.741584. PMID 23137182. 
  5. ^ a b c Dhillon, S; Weber, J. (2009). "Saxagliptin". Drugs 69 (15): 2103–2114. doi:10.2165/11201170-000000000-00000. PMID 19791828. 
  6. ^ "New Drugs: Saxagliptin". Australian Prescriber (34): 89–91. June 2011. 
  7. ^ a b c "Onglyza". RxList. Retrieved 2012-01-31. 
  8. ^ Matveyenko AV, Dry S, Cox HI, et al. (July 2009). "Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin". Diabetes 58 (7): 1604–15. doi:10.2337/db09-0058. PMC 2699878. PMID 19403868. 
  9. ^ Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC (July 2013). "Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors". Diabetes 62 (7): 2595–604. doi:10.2337/db12-1686. PMID 23524641. 
  10. ^ "Pancreatic Safety of Incretin-Based Drugs — FDA and EMA Assessment — NEJM". 
  11. ^ "Latest Januvia Lawsuits Alleging Pancreatic Cancer Help: Resource4thePeople Reports Cases Continue To Be Filed in Federal Multidistrict Litigation". DG. DigitalJournal.com. October 14, 2013. Retrieved 2013-10-14. 
  12. ^ "IN RE: INCRETIN MIMETICS PRODUCTS LIABILITY LITIGATION". USJP. United States Judicial Panel on Multidistric Litigation. August 26, 2013. Retrieved 2013-08-26. 
  13. ^ Savage, Scott A.; Jones, Gregory S.; Kolotuchin, Sergei; Ramrattan, Shelly Ann; Vu, Truc; Waltermire, Robert E. (2009). "Preparation of Saxagliptin, a Novel DPP-IV Inhibitor". Org. Process Res. Dev. 13: 091016152805096. doi:10.1021/op900226j. 
  14. ^ [1] Diabetes info
  15. ^ a b Mentlein, R; Gallwitz, B; Schmidt, WE (15 June 1993). "Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum". European Journal of Biochemistry 214 (3): 829–835. doi:10.1111/j.1432-1033.1993.tb17986.x. PMID 8100523. 
  16. ^ Ahrén, Bo; Landin-Olsson, Mona; Jansson, Per-Anders; Svensson, Maria; Holmes, David; Schweizer, Anja (May 2004). "Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes". Journal of Clinical Endocrinology & Metabolism 89 (5): 2078–2084. doi:10.1210/jc.2003-031907. PMID 15126524. Retrieved 2007-01-11. 
  17. ^ Robert Frederich, MD, PhD et al. (May 2010). "A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin Drug Development Program for Type 2 Diabetes". Postgraduate Medicine. 122 (3): 16–27. doi:10.3810/pgm.2010.05.2138. PMID 20463410. 
  18. ^ Telegram (2 August 2009). "FDA approves diabetes drug from two area manufacturers". Worcester Telegram & Gazette Corp. Retrieved 2009-08-02. 
  19. ^ "Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. Announce Exclusive Licensing Agreement for Diabetes Compound Saxagliptin in Japan" (Press release). Bristol-Myers Squibb. December 27, 2006. Retrieved 2006-12-27. 
  20. ^ Associated Press (11 January 2007). "AstraZeneca teams with Bristol-Myers on diabetes drugs". Delaware News-Journal. Retrieved 2007-01-11. dead link

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