Identification

Name
Alogliptin
Accession Number
DB06203
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
Synonyms
  • Alogliptina
  • Alogliptine
  • Alogliptinum
Product Ingredients
IngredientUNIICASInChI Key
Alogliptin benzoateEEN99869SC850649-62-6KEJICOXJTRHYAK-XFULWGLBSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NesinaTablet, film coated6.25 mg/1OralTakeda2013-01-25Not applicableUs
NesinaTablet6.25 mgOralTakeda2014-04-30Not applicableCanada
NesinaTablet, film coated25 mg/1OralTakeda2013-01-25Not applicableUs
NesinaTablet25 mgOralTakeda2014-05-13Not applicableCanada
NesinaTablet, film coated12.5 mg/1OralTakeda2013-01-25Not applicableUs
NesinaTablet12.5 mgOralTakeda2014-04-30Not applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AlogliptinTablet, film coated6.25 mg/1OralPerrigo New York Inc.2016-04-08Not applicableUs
AlogliptinTablet, film coated25 mg/1OralPerrigo New York Inc.2016-04-08Not applicableUs
AlogliptinTablet, film coated12.5 mg/1OralPerrigo New York Inc.2016-04-08Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Alogliptin and Metformin HydrochlorideAlogliptin benzoate (12.5 mg/1) + Metformin Hydrochloride (500 mg/1)Tablet, film coatedOralPerrigo New York Inc.2016-04-08Not applicableUs
Alogliptin and Metformin HydrochlorideAlogliptin benzoate (12.5 mg/1) + Metformin Hydrochloride (1000 mg/1)Tablet, film coatedOralPerrigo New York Inc.2016-04-08Not applicableUs
Alogliptin and PioglitazoneAlogliptin benzoate (25 mg/1) + Pioglitazone Hydrochloride (15 mg/1)Tablet, film coatedOralPerrigo New York Inc.2016-04-08Not applicableUs
Alogliptin and PioglitazoneAlogliptin benzoate (12.5 mg/1) + Pioglitazone Hydrochloride (30 mg/1)Tablet, film coatedOralPerrigo New York Inc.2016-04-08Not applicableUs
Alogliptin and PioglitazoneAlogliptin benzoate (25 mg/1) + Pioglitazone Hydrochloride (30 mg/1)Tablet, film coatedOralPerrigo New York Inc.2016-04-08Not applicableUs
Alogliptin and PioglitazoneAlogliptin benzoate (12.5 mg/1) + Pioglitazone Hydrochloride (15 mg/1)Tablet, film coatedOralPerrigo New York Inc.2016-04-08Not applicableUs
Alogliptin and PioglitazoneAlogliptin benzoate (25 mg/1) + Pioglitazone Hydrochloride (45 mg/1)Tablet, film coatedOralPerrigo New York Inc.2016-04-08Not applicableUs
Alogliptin and PioglitazoneAlogliptin benzoate (12.5 mg/1) + Pioglitazone Hydrochloride (45 mg/1)Tablet, film coatedOralPerrigo New York Inc.2016-04-08Not applicableUs
IncresyncAlogliptin (12.5 mg) + Pioglitazone (45 mg)Tablet, film coatedOralTakeda Pharma A/S2013-09-19Not applicableEu
IncresyncAlogliptin (12.5 mg) + Pioglitazone (30 mg)Tablet, film coatedOralTakeda Pharma A/S2013-09-19Not applicableEu
Categories
UNII
JHC049LO86
CAS number
850649-61-5
Weight
Average: 339.3916
Monoisotopic: 339.169524941
Chemical Formula
C18H21N5O2
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

Pharmacology

Indication

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

Associated Conditions
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
Human
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.

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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Alogliptin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Alogliptin.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Alogliptin is combined with 2,4-thiazolidinedione.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Alogliptin.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Alogliptin.
4-MethoxyamphetamineThe metabolism of Alogliptin can be decreased when combined with 4-Methoxyamphetamine.
5-(2-methylpiperazine-1-sulfonyl)isoquinolineThe therapeutic efficacy of Alogliptin can be increased when used in combination with 5-(2-methylpiperazine-1-sulfonyl)isoquinoline.
5-androstenedioneThe metabolism of Alogliptin can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Alogliptin can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Alogliptin.
Food Interactions
Not Available

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. [PubMed:18405789]
  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. [PubMed:18405788]
  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. [PubMed:22686547]
External Links
KEGG Drug
D06553
PubChem Compound
11450633
PubChem Substance
175427056
ChemSpider
9625485
BindingDB
16285
ChEBI
72323
ChEMBL
CHEMBL376359
HET
T22
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Alogliptin
ATC Codes
A10BD13 — Metformin and alogliptinA10BD09 — Pioglitazone and alogliptinA10BH04 — Alogliptin
AHFS Codes
  • 68:20.05 — Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
PDB Entries
3g0b
FDA label
Download (648 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailablePharmacokinetics and Pharmacodynamics1
1CompletedNot AvailableType 2 Diabetes Mellitus1
1CompletedOtherHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentType 2 Diabetes Mellitus1
2CompletedTreatmentDiabetes Mellitus (DM)1
2CompletedTreatmentType 2 Diabetes Mellitus2
2TerminatedTreatmentDiabetes Mellitus (DM)1
2, 3CompletedTreatmentType 2 Diabetes Mellitus7
3CompletedNot AvailableDiabetes Mellitus (DM)2
3CompletedTreatmentAcute Coronary Syndromes (ACS) / Type 2 Diabetes Mellitus1
3CompletedTreatmentDiabetes Mellitus (DM)12
3CompletedTreatmentDiabetes Mellitus (DM) / Type 2 Diabetes Mellitus1
3CompletedTreatmentType 2 Diabetes Mellitus4
3RecruitingTreatmentType 2 Diabetes Mellitus1
4CompletedTreatmentInsulin Resistance / Polycystic Ovaries Syndrome1
4CompletedTreatmentType 2 Diabetes Mellitus2
4Not Yet RecruitingTreatmentType 2 Diabetes Mellitus1
4RecruitingTreatmentType 2 Diabetes Mellitus2
4WithdrawnTreatmentType 2 Diabetes Mellitus1
Not AvailableCompletedNot AvailableDiabetes Mellitus (DM)1
Not AvailableCompletedNot AvailablePatients With Type 2 Diabetes Mellitus Who Have Been Examined at a Medical Institution / Type 2 Diabetes Mellitus Who Have Been Examined at a Medical Institution1
Not AvailableCompletedNot AvailableSurveillance3
Not AvailableCompletedNot AvailableType 2 Diabetes Mellitus3
Not AvailableCompletedTreatmentType 2 Diabetes Mellitus1
Not AvailableNot Yet RecruitingNot AvailableType 2 Diabetes Mellitus1
Not AvailableRecruitingNot AvailableType 2 Diabetes Mellitus1
Not AvailableTerminatedNot AvailableType 2 Diabetes Mellitus1
Not AvailableUnknown StatusTreatmentType 2 Diabetes Mellitus1

Pharmacoeconomics

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

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
Polarizability35.44 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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Benzonitrile / Dialkylarylamine / 3-aminopiperidine / Aminopyrimidine / Pyrimidone / Hydropyrimidine / Piperidine / Pyrimidine / Heteroaromatic compound / Vinylogous amide
show 17 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
piperidines, pyrimidines, primary amino compound, nitrile (CHEBI:72323)

Targets

Details
1. Dipeptidyl peptidase 4
Kind
Protein
Organism
Human
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

Enzymes

Kind
Protein
Organism
Human
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
Human
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 on March 19, 2008 10:17 / Updated on November 18, 2018 13:32