Alogliptin

Identification

Summary

Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to treat hyperglycemia in patients with type 2 diabetes mellitus.

Brand Names
Incresync, Kazano, Nesina, Oseni
Generic Name
Alogliptin
DrugBank Accession Number
DB06203
Background

Alogliptin is a selective, orally-bioavailable inhibitor of enzymatic activity of dipeptidyl peptidase-4 (DPP-4). Chemically, alogliptin is prepared as a benzoate salt and exists predominantly as the R-enantiomer (>99%). It undergoes little or no chiral conversion in vivo to the (S)-enantiomer. FDA approved January 25, 2013.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 339.3916
Monoisotopic: 339.169524941
Chemical Formula
C18H21N5O2
Synonyms
  • Alogliptin
  • Alogliptina
  • Alogliptine
  • Alogliptinum

Pharmacology

Indication

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used as adjunct in combination to manageType 2 diabetes mellitusCombination Product in combination with: Pioglitazone (DB01132)••••••••••••
Used as adjunct in combination to manageType 2 diabetes mellitusCombination Product in combination with: Metformin (DB00331)••••••••••••
Management ofType 2 diabetes mellitus••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Peak inhibition of DPP-4 occurs within 2-3 hours after a single-dose administration to healthy subjects. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Alogliptin also demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an 8-hour period following a standardized meal. Alogliptin does not affect the QTc interval.

Mechanism of action

Alogliptin inhibits dipeptidyl peptidase 4 (DPP-4), which normally degrades the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide 1 ( GLP-1). The inhibition of DPP-4 increases the amount of active plasma incretins which helps with glycemic control. GIP and GLP-1 stimulate glucose dependent secretion of insulin in pancreatic beta cells. GLP-1 has the additional effects of suppressing glucose dependent glucagon secretion, inducing satiety, reducing food intake, and reducing gastric emptying.

TargetActionsOrganism
ADipeptidyl peptidase 4
inhibitor
Humans
Absorption

The pharmacokinetics of NESINA was also shown to be similar in healthy subjects and in patients with type 2 diabetes. When single, oral doses up to 800 mg in healthy subjects and type 2 diabetes patients are given, the peak plasma alogliptin concentration (median Tmax) occurred 1 to 2 hours after dosing. Accumulation of aloglipin is minimal. The absolute bioavailability of NESINA is approximately 100%. Food does not affect the absorption of alogliptin.

Volume of distribution

Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues.

Protein binding

Alogliptin is 20% bound to plasma proteins.

Metabolism

Alogliptin does not undergo extensive metabolism. Two minor metabolites that were detected are N-demethylated alogliptin (<1% of parent compound) and N-acetylated alogliptin (<6% of parent compound). The N-demethylated metabolite is active and an inhibitor of DPP-4. The N-acetylated metabolite is inactive. Cytochrome enzymes that are involved with the metabolism of alogliptin are CYP2D6 and CYP3A4 but the extent to which this occurs is minimal. Approximately 10-20% of the dose is hepatically metabolized by cytochrome enzymes.

Route of elimination

Renal excretion (76%) and feces (13%). 60% to 71% of the dose is excreted as unchanged drug in the urine.

Half-life

Terminal half-life = 21 hours

Clearance

Renal clearance = 9.6 L/h (this value indicates some active renal tubular secretion); Systemic clearance = 14.0 L/h.

Adverse Effects
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Toxicity

Common adverse reactions (reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo) are: nasopharyngitis, headache, and upper respiratory tract infection.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Alogliptin which could result in a higher serum level.
AbametapirThe serum concentration of Alogliptin can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Alogliptin can be increased when combined with Abatacept.
AbirateroneThe metabolism of Alogliptin can be decreased when combined with Abiraterone.
AcarboseThe risk or severity of hypoglycemia can be increased when Acarbose is combined with Alogliptin.
Food Interactions
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Alogliptin benzoateEEN99869SC850649-62-6KEJICOXJTRHYAK-XFULWGLBSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NesinaTablet25 mgOralTakeda2014-05-13Not applicableCanada flag
NesinaTablet, film coated25 mg/1OralTakeda Pharmaceuticals America, Inc.2013-01-25Not applicableUS flag
NesinaTablet12.5 mgOralTakeda2014-04-30Not applicableCanada flag
NesinaTablet, film coated12.5 mg/1OralTakeda Pharmaceuticals America, Inc.2013-01-25Not applicableUS flag
NesinaTablet6.25 mgOralTakeda2014-04-30Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AlogliptinTablet, film coated12.5 mg/1OralAphena Pharma Solutions - Tennessee, LLC2016-04-08Not applicableUS flag
AlogliptinTablet, film coated12.5 mg/1OralPadagis Israel Pharmaceuticals Ltd2016-04-08Not applicableUS flag
AlogliptinTablet, film coated25 mg/1OralA-S Medication Solutions2016-04-08Not applicableUS flag
AlogliptinTablet, film coated6.25 mg/1OralPadagis Israel Pharmaceuticals Ltd2016-04-08Not applicableUS flag
AlogliptinTablet, film coated25 mg/1OralREMEDYREPACK INC.2024-01-06Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Alogliptin and Metformin HydrochlorideAlogliptin benzoate (12.5 mg/1) + Metformin hydrochloride (1000 mg/1)Tablet, film coatedOralA-S Medication Solutions2016-04-08Not applicableUS flag
Alogliptin and Metformin HydrochlorideAlogliptin benzoate (12.5 mg/1) + Metformin hydrochloride (500 mg/1)Tablet, film coatedOralPadagis Israel Pharmaceuticals Ltd2016-04-08Not applicableUS flag
Alogliptin and Metformin HydrochlorideAlogliptin benzoate (12.5 mg/1) + Metformin hydrochloride (1000 mg/1)Tablet, film coatedOralPadagis Israel Pharmaceuticals Ltd2016-04-08Not applicableUS flag
Alogliptin and PioglitazoneAlogliptin benzoate (25 mg/1) + Pioglitazone hydrochloride (45 mg/1)Tablet, film coatedOralPadagis Israel Pharmaceuticals Ltd2016-04-08Not applicableUS flag
Alogliptin and PioglitazoneAlogliptin benzoate (12.5 mg/1) + Pioglitazone hydrochloride (30 mg/1)Tablet, film coatedOralPadagis Israel Pharmaceuticals Ltd2016-04-08Not applicableUS flag

Categories

ATC Codes
A10BD13 — Metformin and alogliptinA10BD09 — Pioglitazone and alogliptinA10BH04 — Alogliptin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzonitriles. These are organic compounds containing a benzene bearing a nitrile substituent.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzonitriles
Direct Parent
Benzonitriles
Alternative Parents
Dialkylarylamines / Pyrimidones / Aminopiperidines / Aminopyrimidines and derivatives / Hydropyrimidines / Vinylogous amides / Heteroaromatic compounds / Ureas / Lactams / Azacyclic compounds
show 6 more
Substituents
3-aminopiperidine / Amine / Aminopyrimidine / Aromatic heteromonocyclic compound / Azacycle / Benzonitrile / Carbonitrile / Dialkylarylamine / Heteroaromatic compound / Hydrocarbon derivative
show 17 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
piperidines, pyrimidines, primary amino compound, nitrile (CHEBI:72323)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
JHC049LO86
CAS number
850649-61-5
InChI Key
ZSBOMTDTBDDKMP-OAHLLOKOSA-N
InChI
InChI=1S/C18H21N5O2/c1-21-17(24)9-16(22-8-4-7-15(20)12-22)23(18(21)25)11-14-6-3-2-5-13(14)10-19/h2-3,5-6,9,15H,4,7-8,11-12,20H2,1H3/t15-/m1/s1
IUPAC Name
2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}methyl)benzonitrile
SMILES
CN1C(=O)C=C(N2CCC[C@@H](N)C2)N(CC2=C(C=CC=C2)C#N)C1=O

References

Synthesis Reference

Kenji Nakamura, Kenichiro Kiyoshima, Junya Nomura, "SOLID PREPARATION COMPRISING ALOGLIPTIN AND PIOGLITAZONE." U.S. Patent US20100092551, issued April 15, 2010.

US20100092551
General References
  1. Christopher R, Covington P, Davenport M, Fleck P, Mekki QA, Wann ER, Karim A: Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects. Clin Ther. 2008 Mar;30(3):513-27. doi: 10.1016/j.clinthera.2008.03.005. [Article]
  2. Covington P, Christopher R, Davenport M, Fleck P, Mekki QA, Wann ER, Karim A: Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. Clin Ther. 2008 Mar;30(3):499-512. doi: 10.1016/j.clinthera.2008.03.004. [Article]
  3. Golightly LK, Drayna CC, McDermott MT: Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet. 2012 Aug 1;51(8):501-14. doi: 10.2165/11632930-000000000-00000. [Article]
KEGG Drug
D06553
PubChem Compound
11450633
PubChem Substance
175427056
ChemSpider
9625485
BindingDB
16285
RxNav
1368001
ChEBI
72323
ChEMBL
CHEMBL376359
ZINC
ZINC000014961096
PDBe Ligand
T22
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Alogliptin
PDB Entries
3g0b
FDA label
Download (648 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentType 2 Diabetes Mellitus1
4CompletedTreatmentDiabetes Mellitus1
4CompletedTreatmentPolycystic Ovarian Syndrome (PCOS) / Resistance, Insulin1
4CompletedTreatmentType 2 Diabetes Mellitus4
4TerminatedTreatmentType 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral8.500 mg
Tablet, coatedOral
TabletOral
Tablet, film coatedOral
TabletOral12.5 mg
TabletOral25 mg
TabletOral6.25 mg
Tablet, film coatedOral
Tablet, film coatedOral12.5 mg/1
Tablet, film coatedOral25 mg/1
Tablet, film coatedOral6.25 mg/1
Tablet, film coatedOral12.5 mg
Tablet, film coatedOral12.5 MG
Tablet, film coatedOral25 MG
Tablet, film coatedOral6.25 MG
Tablet, coatedOral12.5 mg
Tablet, film coatedOral25 mg
Tablet, coatedOral25 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6150383No2000-11-212016-06-19US flag
US6211205No2001-04-032016-06-19US flag
US6303640No2001-10-162016-08-09US flag
US6329404No2001-12-112016-06-19US flag
US5965584No1999-10-122016-06-19US flag
US6166042No2000-12-262016-06-19US flag
US6166043No2000-12-262016-06-19US flag
US6172090No2001-01-092016-06-19US flag
US6150384No2000-11-212016-06-19US flag
US6271243No2001-08-072016-06-19US flag
US6303661No2001-10-162017-04-24US flag
US6890898No2005-05-102019-02-02US flag
US7078381No2006-07-182019-02-02US flag
US7459428No2008-12-022019-02-02US flag
US7807689No2010-10-052028-06-27US flag
US8173663No2012-05-082025-03-15US flag
US8288539No2012-10-162025-03-15US flag
US8697125No2014-04-152029-01-22US flag
US8637079No2014-01-282029-06-04US flag
US8900638No2014-12-022029-05-24US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySparingly soluble FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.58 mg/mLALOGPS
logP0.66ALOGPS
logP1.16Chemaxon
logS-2.8ALOGPS
pKa (Strongest Basic)9.47Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area93.67 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity104.26 m3·mol-1Chemaxon
Polarizability35.64 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9942
Blood Brain Barrier+0.9738
Caco-2 permeable-0.5492
P-glycoprotein substrateSubstrate0.6453
P-glycoprotein inhibitor INon-inhibitor0.6811
P-glycoprotein inhibitor IINon-inhibitor0.9238
Renal organic cation transporterNon-inhibitor0.591
CYP450 2C9 substrateNon-substrate0.8003
CYP450 2D6 substrateNon-substrate0.7259
CYP450 3A4 substrateSubstrate0.5528
CYP450 1A2 substrateNon-inhibitor0.9169
CYP450 2C9 inhibitorNon-inhibitor0.8475
CYP450 2D6 inhibitorNon-inhibitor0.9038
CYP450 2C19 inhibitorNon-inhibitor0.8527
CYP450 3A4 inhibitorNon-inhibitor0.7608
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9363
Ames testNon AMES toxic0.5595
CarcinogenicityNon-carcinogens0.8887
BiodegradationNot ready biodegradable0.9931
Rat acute toxicity2.5603 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.5507
hERG inhibition (predictor II)Inhibitor0.8389
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0009000000-b5c5f94cc839f451b69b
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-0029000000-48f483b2435f3c867cd9
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0019000000-f92369c484f34d437f26
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0079-0097000000-bdccfdbe30c695befcac
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-059y-5693000000-ec84fbf390d84c0a3e32
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0159-0491000000-57fc6770a9441a66ad54
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-193.9398697
predicted
DarkChem Lite v0.1.0
[M-H]-175.75768
predicted
DeepCCS 1.0 (2019)
[M+H]+195.0411697
predicted
DarkChem Lite v0.1.0
[M+H]+178.11568
predicted
DeepCCS 1.0 (2019)
[M+Na]+194.2153697
predicted
DarkChem Lite v0.1.0
[M+Na]+185.73883
predicted
DeepCCS 1.0 (2019)

Targets

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Details
1. Dipeptidyl peptidase 4
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Virus receptor activity
Specific Function
Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by bindi...
Gene Name
DPP4
Uniprot ID
P27487
Uniprot Name
Dipeptidyl peptidase 4
Molecular Weight
88277.935 Da
References
  1. Nadkarni P, Chepurny OG, Holz GG: Regulation of glucose homeostasis by GLP-1. Prog Mol Biol Transl Sci. 2014;121:23-65. doi: 10.1016/B978-0-12-800101-1.00002-8. [Article]
  2. Gallwitz B: Novel Therapeutic Approaches in Diabetes. Endocr Dev. 2016;31:43-56. doi: 10.1159/000439372. Epub 2016 Jan 19. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da

Drug created at March 19, 2008 16:17 / Updated at March 18, 2024 16:48