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Saxagliptin
Systematic (IUPAC) name
	(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl); acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile
Identifiers
CAS number	361442-04-8
ATC code	none
PubChem	6451162
Chemical data
Formula	C18H25N3O2
Mol. mass	315.41 g/mol
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	?

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] It was developed by Bristol-Myers Squibb. In June 2008, it was announced that Onglyza would be the trade name under which saxagliptin will be marketed^[2].

The FDA approved Onglyza on July 31, 2009^[3].

Dipeptidyl peptidase-4's role in blood glucose regulation is thought to be through degradation of GIP^[4] and the degradation of GLP-1.^[4]^[5]

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.^[6] 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.^[7]

[edit] 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):^[8]

[edit] Efficacy

Oral saxagliptin 2.5 or 5 mg once daily significantly improved mean HbA1c levels, relative to placebo, in well designed, 24-week trials in treatment-naive patients with type 2 diabetes.^[9] Combination therapy with saxagliptin 5 mg once daily and metformin was more effective than saxagliptin or metformin monotherapy.^[9]

[edit] Tolerability

Both monotherapy and combination therapy with other agents was generally well tolerated in clinical trials.^[9]

[edit] See also

[edit] References

^ 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.
^ Bloomberg.com: U.S
^ Telegram (02 August 2009). "FDA approves diabetes drug from two area manufacturers". Worcester Telegram & Gazette Corp.. http://www.telegram.com/article/20090802/NEWS/908020328/1002. Retrieved 2009-08-02.
^ ^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.
^ 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. http://jcem.endojournals.org/cgi/content/full/89/5/2078. Retrieved 2007-01-11.
^ Bristol-Myers Squibb (December 27, 2006). "Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. Announce Exclusive Licensing Agreement for Diabetes Compound Saxagliptin in Japan". Press release. http://investor.bms.com/phoenix.zhtml?c=106664&p=irol-newsArticle&ID=944899&highlight=. Retrieved 2006-12-27.
^ Associated Press (11 January 2007). "AstraZeneca teams with Bristol-Myers on diabetes drugs". Delaware News-Journal. http://www.delawareonline.com/apps/pbcs.dll/article?AID=/20070111/BUSINESS/70111024/-1/NLETTER02. Retrieved 2007-01-11.
^ Scott A. Savage, Gregory S. Jones, Sergei Kolotuchin, Shelly Ann Ramrattan, Truc Vu, and Robert E. Waltermire (2009). "Preparation of Saxagliptin, a Novel DPP-IV Inhibitor". Org. Process Res. Dev.: 091016152805096. doi:10.1021/op900226j.
^ ^a ^b ^c Dhillon S, Weber J. Saxagliptin. Drugs 2009; 69 (15): 2103-2114. doi: 10.2165/11201170-000000000-00000.

[edit] External links

Official site
Banting and Best Diabetes Centre at UT dpp4
The race to get DPP-4 inhibitors to market - Forbes.com
Walker, Emily P.. "Saxagliptin First Diabetes Drug to Pass FDA Cardiovascular Safety Review". http://www.medpagetoday.com/Washington-Watch/Washington-Watch/13555.

This pharmacology-related article is a stub. You can help Wikipedia by expanding it.

[ahren-0] 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.

[Bloomberg-1] Bloomberg.com: U.S

[2] Telegram (02 August 2009). "FDA approves diabetes drug from two area manufacturers". Worcester Telegram & Gazette Corp.. http://www.telegram.com/article/20090802/NEWS/908020328/1002. Retrieved 2009-08-02.

[mentlein-3] 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.

[ahren2-4] 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. http://jcem.endojournals.org/cgi/content/full/89/5/2078. Retrieved 2007-01-11.

[5] Bristol-Myers Squibb (December 27, 2006). "Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. Announce Exclusive Licensing Agreement for Diabetes Compound Saxagliptin in Japan". Press release. http://investor.bms.com/phoenix.zhtml?c=106664&p=irol-newsArticle&ID=944899&highlight=. Retrieved 2006-12-27.

[6] Associated Press (11 January 2007). "AstraZeneca teams with Bristol-Myers on diabetes drugs". Delaware News-Journal. http://www.delawareonline.com/apps/pbcs.dll/article?AID=/20070111/BUSINESS/70111024/-1/NLETTER02. Retrieved 2007-01-11.

[7] Scott A. Savage, Gregory S. Jones, Sergei Kolotuchin, Shelly Ann Ramrattan, Truc Vu, and Robert E. Waltermire (2009). "Preparation of Saxagliptin, a Novel DPP-IV Inhibitor". Org. Process Res. Dev.: 091016152805096. doi:10.1021/op900226j.

[saxa-8] Dhillon S, Weber J. Saxagliptin. Drugs 2009; 69 (15): 2103-2114. doi: 10.2165/11201170-000000000-00000.

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