Description
Alogliptin is a dipeptidyl-peptidase IV (DPP-4) inhibitor that was
approved in Japan in 2010 for treatment of type 2 diabetes, a disease in
which insulin resistance and β-cell dysfunction lead to hyperglycemia.
As islet function is lost, the severity of insulin resistance
increases. The introduction of DPP-4 inhibitors has brought a novel
class of insulinotropic agents for the treatment options available to type
2 diabetic patients. The therapeutic potential of glucagon-like peptide 1
(GLP-1), an incretin peptide, for the treatment of type 2 diabetes was
realized in the 1990s. The insulinotropic effects of GLP-1 depend closely
on glucose concentrations providing the possibility of glucose normalization
without the risk of hypoglycemia. GLP-1 has other non-insulinotropic
physiological actions that are advantageous. It suppresses glucagon
secretion from a cells and slows gastric emptying, which contributes to
satiety and to a slower passage and reabsorption of carbohydrates. GLP-1
also contributes to satiety via a central mechanism as a neurotransmitter
with effects on the hypothalamus.
Chemical Properties
White Solid
Originator
Syrrx Inc. (now Takeda San Diego) (Japan)
Uses
Alogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4).
Antidiabetic agent.
Definition
ChEBI: A piperidine that is 3-methyl-2,4-dioxo-3,4-dihydropyrimidine carrying additional 2-cyanobenzyl and 3-aminopiperidin-1-yl groups at positions 1 and 2 respectively (the R-enantiomer). Used in the form of its benzoate salt for treatment of t
pe 2 diabetes.
Clinical Use
Dipeptidyl peptidase 4 inhibitor:
Treatment of type 2 diabetes in combination with
other therapies
Synthesis
To the reaction flask was added 160.0 g (0.36 mol) of alogliptin precursor (III) and 2 L of methanol and stirred until complete dissolution. Subsequently, 46.0 g of trifluoroacetic acid was added and the reaction mixture was stirred at 65 °C for 7 h. The reaction was monitored by TLC until completion. After completion of the reaction, the reaction solution was slowly added dropwise to 2 L of water under stirring and stirring was continued for 30 minutes. The precipitate was collected by filtration and the filter cake was mixed with saturated sodium bicarbonate solution and stirred for 30 minutes to neutralize. The filter was again filtered and the filter cake was washed with water. Finally, recrystallization was carried out using a mixed isopropanol-ethanol solvent to give a white solid product. The product was dried under vacuum at 60 °C for 12 h to give 102.5 g of (R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile in 83% yield, 98.9% purity, and a melting point of 126~128 °C.
Enzyme inhibitor
This orally available DPP-IV inhibitor (FW = 339.39 g/mol; CAS 850649-
62-6), also known as 2- ({6-[ (3R) -3-aminopiperidin-1-yl]-3-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1 (2H) -yl}methyl) benzonitrile and by its trade
name Nesina? targets dipeptidyl peptidase IV, or DPP-4, thereby retarding
the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and
GIP (glucose-dependent insulinotropic peptide), both of which play a role
in regulating blood glucose levels. Alogliptin inhibition is competitive,
Ki = 24 nM. In 2013, alogliptin received FDA approval for the
treatment of type II diabetes mellitus. DPP-4 inhibitors have become
widely accepted in clinical practice because of their low risk of
hypoglycemia, favorable adverse-effect profile, and once-daily dosing. The
only reported side-effect is mild hypoglycemia, suggesting that some
individuals may benefit from a slightly lower dose. Other DPP-4 inhibitors
include sitagliptin phosphate (Januvia?) and saxagliptin (Onglyza?). DPP-4
inhibition has been associated with enhanced β-cell survival and neogenesis
in streptozotocin-treated diabetic rats (See also Streptozotocin).
Significantly, the addition of alogliptin resulted in clinically significant
reductions in HbA1c (typically from 1.4 to 1%), without increased incidence
of hypoglycemia, in type 2 diabetes patients who are inadequately
controlled by glyburide monotherapy.
Drug interactions
Potentially hazardous interactions with other drugs
None known
Metabolism
Alogliptin does not undergo extensive metabolism. Two
minor metabolites were detected following administration
of an oral dose of [14C]-alogliptin, N-demethylated
alogliptin, M-I (<1% of the parent compound), and
N-acetylated alogliptin, M-II (<6% of the parent
compound). M-I is an active metabolite and is a highly
selective inhibitor of DPP-4 similar to alogliptin; M-II
does not display any inhibitory activity towards DPP-4
or other DPP-related enzymes. In vitro data indicate
that CYP2D6 and CYP3A4 contribute to the limited
metabolism of alogliptin.
References
[1] Patent: CN104086527, 2016, B. Location in patent: Paragraph 0052; 0061-0063; 0074
[2] Patent: CN105777709, 2016, A. Location in patent: Paragraph 0069; 0070
[3] Patent: CN106336396, 2017, A. Location in patent: Paragraph 0013-0119
[4] Patent: WO2015/92807, 2015, A1. Location in patent: Sheet 8
[5] Patent: CN103910710, 2017, B. Location in patent: Paragraph 0064-0065
![2-[[6-[(3R)-3-tert-butoxycarbonylamino-1-piperidinyl]-3,4-dihydro-2,4-dioxo-3-methyl-1(2H)-pyrimidinyl]methyl]benzonitrile](/CAS/20180703/GIF/1246610-74-1.gif)
