486460-32-6 Usage
Description
Different sources of media describe the Description of 486460-32-6 differently. You can refer to the following data:
1. Sitagliptin is an orally-bioavailable selective DPP4 inhibitor that was discovered through the optimization of a class of β-aminoacid-derived DPP4 inhibitors. It lowers DPP4 activity in a sustained manner following once daily administration, preserves the circulating levels of intact GIP and GLP1 following meals in both acute and chronic studies and reduces blood glucose levels without significant increases in hypoglycaemia.
Sitagliptin phosphate (STG) is used to treat DM type 2 because it improves glycemic control by increasing the levels of active incretin hormones, GLP-1 (peptide-1) and GIP (glucose-dependent insulinotropic peptide). The activation of these incretins in β-pancreatic cells causes increased levels of cyclic adenosine monophosphate (cAMP) and intracellular calcium, with subsequent glucose-dependent insulin secretion (2). This hypoglycemic drug belongs to a new class called dipeptidyl peptidase IV inhibitors. STG was approved by the FDA in 2006.
2. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a first-in-class oral
drug launched for the treatment of type 2 diabetes. It acts by slowing the
inactivation of incretins, which are endogenous peptides involved in the physiologic
regulation of glucose homeostasis. Incretin hormones, including glucagonlike
peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP),
are released by the intestine throughout the day, and levels are increased in
response to a meal. When blood glucose concentrations are normal or elevated,GLP-1 and GIP increase the synthesis and release of insulin from pancreatic b
cells via intracellular signaling pathways involving cAMP. GLP-1 also lowers
glucagon secretion from pancreatic αcells, which leads to reduced hepatic
glucose production.
Mechanism of action
Sitagliptin prolongs the activity of proteins that increase the release of insulin after blood sugar rises, such as after a meal. Sitagliptin is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), which metabolizes the naturally occurring incretin hormones glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) resulting in enhanced glucose-dependent insulin secretion from the pancreas and decreased hepatic glucose production. Since GLP-1 enhances insulin secretion in the presence of raised blood glucose levels, inhibiting DPP-IV activity will increase and prolong the action of GLP-1 by reducing its rate of inactivation in plasma. Sitagliptin reduces hemoglobin A1c (HbA1c), fasting and postprandial glucose by glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. GLP-1 has other widespread effects including delaying gastric emptying, significantly reducing glucagons levels and possible central effects on the appetite.
Pharmacokinetics
Bioavailability of sitagliptin is approximately 87%. Halflife is between 8-14 hours. It is 38% bound to plasma proteins. It undergoes limited metabolism via CYP3A4 and CYP2C8. Elimination is mainly through urine.
Indications
Sitagliptin is approved by the FDA as an adjunct to diet and exercise to improve glycaemic control in patients with T2DM, either as a monotherapy, or in combination with metformin or a peroxisome proliferatoractivated receptor-γ agonist (for example, thiazolidinediones) when the single agent does not provide adequate glycaemic control.
Clinical Use
Different sources of media describe the Clinical Use of 486460-32-6 differently. You can refer to the following data:
1. In October 2006, the U.S. Food and Drug Administration (FDA) approved sitagliptin as monotherapy and as add-on therapy to either of two other types of oral diabetes medications, metformin or thiazolidinediones to improve blood glucose control in patients with type 2 diabetes when diet and exercise are not enough. In March, 2007 it was approved in European Union. Sitagliptin is currently approved in 42 countries. The recommended dose of sitagliptin is 100 mg once daily. It may be taken with or without food. In April, 2007 FDA approved the combination product of sitaglibtin and metformin for type 2 diabetes. In clinical trials of 1-year duration, sitagliptin improved glycaemic control by reducing both fasting and postprandial glucose concentrations, leading to clinically meaningful reductions in glycosylated haemoglobin levels. Monotherapy with sitagliptin 100mg daily decreases mean HbA1c by 0.6- 0.79% (mean difference from placebo). When used in combination with metformin or pioglitazone, the mean reduction is HbA1c is 0.7% and 0.9% respectively. Sitagliptin is considered to be weight neutral and lipid neutral.
2. Treatment of type 2 diabetes in combination with
metformin or a thiazolidinedione
Side effects
In clinical trials, sitagliptin demonstrated an overall incidence of side effects comparable to placebo. The most common side effects in studies were upper respiratory tract infection, stuffy or running nose, sore throat, headache and diarrhea. The incidence of hypoglycemia with sitagliptin monotherapy was not significantly different than placebo. Pooled data from 2 monotherapy and 2 combination trials show that the incidence of hypoglycemia was 1.2% and 0.9% for sitagliptin 100mg and placebo respectively.
Drug interactions
Different sources of media describe the Drug interactions of 486460-32-6 differently. You can refer to the following data:
1. Sitagliptin plasma concentrations may be increased modestly (approximately 68%), with cyclosporine which is not expected to be clinically important. Digoxin plasma levels may be increased slightly (approximately 18%), no dosage adjustment is recommended. Although sitagliptin is not as likely to cause hypoglycemia as some other oral diabetes medications, be careful while prescribing any other drug that can potentially lower blood sugar, such as: probenecid, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin or other salicylates, sulfa drugs, a monoamine oxidase inhibitor (MAOI) or beta-blockers.
2. Potentially hazardous interactions with other drugs
None known
Uses
Different sources of media describe the Uses of 486460-32-6 differently. You can refer to the following data:
1. Sitagliptin is a useful pharmaceutical drug. Could be useful for treating intestinal inflammation, diabetes, pre-?diabetes, impaired glucose tolerance, hepatitis, and?/or inflammatory liver disease.
2. Labeled Sitagliptin , intended for use as an internal standard for the quantification of Sitagliptin by GC- or LC-mass spectrometry.
Definition
ChEBI: Sitagliptin is a triazolopyrazine that exhibits hypoglycemic activity. It has a role as a serine proteinase inhibitor, a hypoglycemic agent, an EC 3.4.14.5 (dipeptidyl-peptidase IV) inhibitor, an environmental contaminant and a xenobiotic. It is a triazolopyrazine and a trifluorobenzene.
Brand name
Januvia
Metabolism
Sitagliptin undergoes minimal metabolism, mainly by the
cytochrome P450 isoenzyme CYP3A4, and to a lesser
extent by CYP2C8.
Renal excretion of sitagliptin involves active tubular
secretion; it is a substrate for organic anion transporter-3
and P-glycoprotein.
Check Digit Verification of cas no
The CAS Registry Mumber 486460-32-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 4,8,6,4,6 and 0 respectively; the second part has 2 digits, 3 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 486460-32:
(8*4)+(7*8)+(6*6)+(5*4)+(4*6)+(3*0)+(2*3)+(1*2)=176
176 % 10 = 6
So 486460-32-6 is a valid CAS Registry Number.
InChI:InChI=1/C16H15F6N5O/c17-10-6-12(19)11(18)4-8(10)3-9(23)5-14(28)26-1-2-27-13(7-26)24-25-15(27)16(20,21)22/h4,6,9H,1-3,5,7,23H2/t9-/m0/s1
486460-32-6Relevant articles and documents
Highly efficient asymmetric synthesis of sitagliptin
Hansen, Karl B.,Hsiao, Yi,Xu, Feng,Rivera, Nelo,Clausen, Andrew,Kubryk, Michele,Krska, Shane,Rosner, Thorsten,Simmons, Bryon,Balsells, Jaume,Ikemoto, Nori,Sun, Yongkui,Spindler, Felix,Malan, Christophe,Grabowski, Edward J. J.,Armstrong III, Joseph D.
, p. 8798 - 8804 (2009)
A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/tBu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.
Sitagliptin inhibit human lymphocytes proliferation and Th1/Th17 differentiation in vitro
Pinheiro, Marcelo Maia,Stoppa, Caroline Lais,Valduga, Claudete Justina,Okuyama, Cristina Eunice,Gorj?o, Renata,Pereira, Regina Mara Silva,Diniz, Susana Nogueira
, p. 17 - 24 (2017)
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents that are widely used in clinical practice to improve glycemic control in patients with type 2 diabetes. DPP-4 is also known as lymphocyte cell surface protein, CD26, and plays an important role in T-cell immunity. Recent studies suggest that DPP-4 inhibitors improve beta-cell function and attenuate autoimmunity in type 1 diabetic mouse models. To investigate the direct effect of DPP4 in immune response, human peripheral blood mononuclear cells (PBMC) from healthy volunteers were obtained by Ficoll gradient and cultivated in the absence (control) or presence of phytohemagglutinin (PHA), or stimulated with PHA and treated with sitagliptin. The immune modulation mechanisms analyzed were: cell proliferation, by MTT assay; cytokine quantification by ELISA or cytometric bead array (CBA), Th1/Th2/Th17 phenotyping by flow cytometric analysis and CD26 gene expression by real time PCR. The results showed that sitagliptin treatment inhibited the proliferation of PBMC-PHA stimulated cells in a dose dependent manner and decreased CD26 expression by these cells, suggesting that sitagliptin may interfere in CD26 expression, dimerization and cell signaling. Sitagliptin treatment not only inhibited IL-10 (p?A statistically significant increase (p?a significantly (p?+?IL-17+, T CD4+?IFNgamma+ and T CD4+?IL-4+ cells were significantly reduced (p??0.05) by sitagliptin. Our data demonstrated an immunosuppressive effect of sitagliptin on Th1, Th17 and Th2 lymphocytes differentiation that leads to the generation of regulatory TGF-beta1 secreting cells with low CD26 gene expression that may influence the state of pancreatic beta-cells and controlling DM1 patients.
IMPROVED PROCESS FOR PREPARATION OF SITAGLIPTIN
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Page/Page column 10-15, (2021/12/31)
Provided herein is a process for the preparation of specific enantiomeric Sitagliptin with good chiral purity and higher yield using improved biocatalyst and by engineering an enzyme to mediate the efficient conversion of ketoamide to obtain enantiomerically pure Sitagliptin in presence of an amino group donor.
Synthesis method of sitagliptin free alkali
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Paragraph 0024; 0054-0061, (2021/07/17)
The invention belongs to the field of organic chemistry, and particularly discloses a synthesis method of sitagliptin free alkali. The synthesis method comprises the following specific steps: (1) dissolving (3R)-N-tert-butyloxycarbonyl-3-amino-4-(2,4,5-trifluorophenyl) butyric acid and organic alkali in an organic solvent, adding a phosphorus-containing condensing agent, then adding 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-alpha]pyrazine hydrochloride to prepare a compound represented by a formula (II); and (2) removing t-butyloxycarboryl from the compound shown in the formula II under the action of acid to obtain a compound I namely sitagliptin free alkali. The method is mild in process reaction condition, easy to control, short in reaction time, free of extraction, simple to operate and beneficial to industrial production, and the process cost is reduced; and the prepared compound shown in the formula I is high in yield, high in purity and free of heavy metal residues.