Alogliptin benzoate

Description

Alogliptin benzoate is a selective oral bioinhibitor of dipeptidyl peptidase-4 (DPP-4) enzymatic activity. Chemically, alogliptin is prepared with benzoate, mainly in the R-enantiomeric form (>99%). Alogliptin undergoes little chiral conversion in vivo and converts into the (S)-enantiomer. It is used in conjunction with proper diet and exercise to treat high blood sugar levels caused by type 2 diabetes. Alogliptin helps control blood sugar levels by increasing the substances in the body that cause the pancreas to release more insulin. It also signals the liver to stop producing sugar (glucose) when there is too much sugar in the blood. This medication does not help people with insulin-dependent or type 1 diabetes.

The Uses of Alogliptin benzoate

Alogliptin Benzoate is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). Alogliptin Benzoate is used in the treatment of type 2 diabetes.

Definition

ChEBI: A benzoate salt obtained by combining equimolar amounts of alogliptin and benzoic acid. Used for treatment of type 2 diabetes.

Side Effects

Common side effects of Alogliptin benzoate include: flu-like symptoms, headache, stomach pain or indigestion, diarrhoea, rash or itchy skin. "Hypoglycaemia" may occur when used in combination with other hypoglycaemic agents such as metformin. Serious allergic reactions are rare and may include sudden swelling of the lips, mouth, throat or tongue, shortness of breath or difficulty breathing, tightness in the throat or difficulty swallowing, turning the skin, tongue or lips blue, grey or pale, and dizziness.

Biological Activity

alogliptin is a novel, highly selective and potent inhibitor of serine protease dipeptidylpeptidase-4 (dpp-4) with ic50 value of less than 10 nm [1].alogliptin has been reported to significantly reduce plasma dpp-4 activity and increase active glp-1 levels in a dose-dependent manner in ob/ob mice. besides, alogliptin after 4 weeks administration remarkably reduced non-fasting glycosylated hemoglobin, non-fasting plasma glucose and triglyceride levels, as well as siginificantly increased non-fasting plasma insulin and fasting pancreatic insulin content in ob/ob mice. moreover, alogliptin treated ob/ob mice have shown the increase of early-phase insulin secretion and the decrease of plasma glucose auc [2]

brand name

Nesina; Vipidia

Clinical Use

Alogliptin benzoate is a dipeptidyl peptidase IV (DPPIV) inhibitor discovered by Takeda Pharmaceuticals and approved in Japan in 2010 for the treatment of type II diabetes mellitus. Alogliptin is an oral drug for once a day dosing to complement diet and exercise. Alogliptin is the most selective marketed DPPIV inhibition and has similar PK and PD properties compared to previous entries. The discovery, structure-activity relationship of related analogs, and synthesis of this compound have been recently published.

Synthesis

The most convenient synthesis for scale-up will be highlighted from several published routes. Commercially available 2-cycanobenzyl amine 1 was reacted with methylisocyanate in DCM at ambient temperature to provide N-methyl urea 2 in 85% yield. Reaction of the urea 2 with dimethyl malonate in refluxing ethanol with sodium ethoxide as base gave the cyclized trione 3 in 78-85% yield. The trione 3 was then refluxed in neat POCl3 to provide the penultimate chloride crude 4 in 95% yield which was reacted with Boc-protected diamine 5 in the presense of potassium carbonate in DMF to furnish alogliptin I in 93-96% yield. Treatment of alogliptin with benzoic acid in ethanol at 60-70 ??C followed by crystallization delivered the desired alogliptin benzoate (I).

References

[1] feng j, zhang z, wallace mb, stafford ja, kaldor sw, kassel db, navre m, shi l, skene rj, asakawa t, takeuchi k, xu r, webb dr, gwaltney sl 2nd. discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase iv. j med chem. 2007 may 17;50(10):2297-300.
[2] moritoh y1, takeuchi k, asakawa t, kataoka o, odaka h. chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice. eur j pharmacol. 2008 jul 7;588(2-3):325-32.