Identification

Name
Linagliptin
Accession Number
DB08882
Type
Small Molecule
Groups
Approved
Description

Linagliptin is a DPP-4 inhibitor developed by Boehringer Ingelheim for the treatment of type II diabetes [Wikipedia]. Two pharmacological characteristics that sets linagliptin apart from other DPP-4 inhibitors is that it has a non-linear pharmacokinetic profile and is not primarily eliminated by the renal system. FDA approved on May 2, 2011.

Structure
Thumb
Synonyms
  • (R)-8-(3-Aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione
  • Trajenta
External IDs
BI 1356 / BI 1356 BS / BI-1356 / BI-1356-BS
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TradjentaTablet, film coated5 mg/1OralCardinal Health2011-05-09Not applicableUs00597 0140 30 nlmimage10 ed3d76cb
TradjentaTablet, film coated5 mg/1OralBoehringer Ingelheim2011-05-09Not applicableUs0597 014020180907 15195 v9gh0y
TrajentaTablet, film coated5 mgOralBoehringer Ingelheim2011-08-24Not applicableEu
TrajentaTablet5 mgOralBoehringer Ingelheim (Canada) Ltd Ltee2011-09-13Not applicableCanada
TrajentaTablet, film coated5 mgOralBoehringer Ingelheim2011-08-24Not applicableEu
TrajentaTablet, film coated5 mgOralBoehringer Ingelheim2011-08-24Not applicableEu
TrajentaTablet, film coated5 mgOralBoehringer Ingelheim2011-08-24Not applicableEu
TrajentaTablet, film coated5 mgOralBoehringer Ingelheim2011-08-24Not applicableEu
TrajentaTablet, film coated5 mgOralBoehringer Ingelheim2011-08-24Not applicableEu
TrajentaTablet, film coated5 mgOralBoehringer Ingelheim2011-08-24Not applicableEu
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
GlyxambiLinagliptin (5 mg) + Empagliflozin (10 mg)TabletOralBoehringer Ingelheim (Canada) Ltd Ltee2016-12-21Not applicableCanada
GlyxambiLinagliptin (5 mg/1) + Empagliflozin (25 mg/1)Tablet, film coatedOralBoehringer Ingelheim2015-01-30Not applicableUs
GlyxambiLinagliptin (5 mg/1) + Empagliflozin (10 mg/1)Tablet, film coatedOralBoehringer Ingelheim2015-01-30Not applicableUs0597 018220180913 8702 q7fevz
GlyxambiLinagliptin (5 mg) + Empagliflozin (25 mg)TabletOralBoehringer Ingelheim (Canada) Ltd Ltee2016-12-21Not applicableCanada
JentaduetoLinagliptin (2.5 mg) + Metformin Hydrochloride (1000 mg)Tablet, film coatedOralBoehringer Ingelheim2012-07-20Not applicableEu
JentaduetoLinagliptin (2.5 mg) + Metformin Hydrochloride (850 mg)Tablet, film coatedOralBoehringer Ingelheim2012-07-20Not applicableEu
JentaduetoLinagliptin (2.5 mg) + Metformin Hydrochloride (850 mg)Tablet, film coatedOralBoehringer Ingelheim2012-07-20Not applicableEu
JentaduetoLinagliptin (2.5 mg/1) + Metformin Hydrochloride (1000 mg/1)Tablet, film coatedOralBoehringer Ingelheim2012-02-13Not applicableUs
JentaduetoLinagliptin (2.5 mg) + Metformin Hydrochloride (500 mg)TabletOralBoehringer Ingelheim (Canada) Ltd Ltee2013-04-17Not applicableCanada
JentaduetoLinagliptin (2.5 mg/1) + Metformin Hydrochloride (1000 mg/1)Tablet, film coatedOralPhysicians Total Care, Inc.2012-02-13Not applicableUs
International/Other Brands
Tradjenta
Categories
UNII
3X29ZEJ4R2
CAS number
668270-12-0
Weight
Average: 472.5422
Monoisotopic: 472.23352218
Chemical Formula
C25H28N8O2
InChI Key
LTXREWYXXSTFRX-QGZVFWFLSA-N
InChI
InChI=1S/C25H28N8O2/c1-4-5-13-32-21-22(29-24(32)31-12-8-9-17(26)14-31)30(3)25(35)33(23(21)34)15-20-27-16(2)18-10-6-7-11-19(18)28-20/h6-7,10-11,17H,8-9,12-15,26H2,1-3H3/t17-/m1/s1
IUPAC Name
8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-2,3,6,7-tetrahydro-1H-purine-2,6-dione
SMILES
CC#CCN1C(=NC2=C1C(=O)N(CC1=NC3=C(C=CC=C3)C(C)=N1)C(=O)N2C)N1CCC[C@@H](N)C1

Pharmacology

Indication

Linagliptin is used for the management of type 2 diabetes mellitus.

Associated Conditions
Pharmacodynamics

Linagliptin is a more potent inhibitor of DPP-4 than other drugs that belong to the same class with an IC50 of 1 nM. In comparison, sitagliptin, saxagliptin, and vildagliptin have an IC50 of 19, 50, and 62 nM respectively. A dose of 2.5 and 5 mg reduces the activity of DPP-4 by 72.7% and 86.1% from baseline respectively in healthy male subjects. In diabetes patients, a dose of 5 and 10 mg inhibits >90% of DPP-4. Linagliptin is also selectively inhibits DPP-4 as indicated by the lack of DPP-8 or DPP-9 inhibition at therapeutic exposures in vitro.

Mechanism of action

Linagliptin is a competitive and reversible dipeptidyl peptidase (DPP)-4 enzyme inhibitor that slows the breakdown of insulinotropic hormone glucagon-like peptide (GLP)-1 for better glycemic control in diabetes patients. GLP and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that increase the production and release of insulin from pancreatic beta cells and decrease the release of glucagon from pancreatic alpha cells. This results in a overall decrease in glucose production in the liver and increase an of insulin in a glucose-dependent manner.

TargetActionsOrganism
ADipeptidyl peptidase 4
inhibitor
Human
Absorption

Cmax, 5 mg, healthy subjects = 8.32 nmol/L; Tmax, 5 mg, healthy subjects = 1.75 hours; AUC(0-24 hours), 5 mg, healthy subjects = 119 nmol · h/L; Bioavailability, healthy subjects = 30%. When a dose of 5 mg once daily is given, steady state is achieved by the third dose. Although a high fat meal reduces Cmax and increases AUC, this interaction with food is not clinically significant. Linagliptin may be administered with or without food.

Volume of distribution

Vd = 1110 L

Protein binding

70-80% protein bound, the extent to which is concentration dependent. Because of the propensity of linagliptin to bind to plasma protein, it has a long terminal half-life and a non-linear pharmacokinetic profile. In contrast, other DPP-4 inhibitors have linear pharmacokinetic profiles which makes linagliptin unique.

Metabolism

Linagliptin is not extensively metabolized, 90% of dose is excreted unchanged. The small portion of drug that is metabolized, the main metabolite is CD 1790 and is pharmacologically inactive. Glucuronidation forms some of its other minor metabolites.

Route of elimination

Linagliptin is eliminated via the feces/enteroheptic system (80%) and urine (5%). This is unlike other DPP-4 inhibitors which are primarily eliminated by the renal system.

Half life

Terminal half life = 131 hours. Because of this long half-life, inhibition of DPP-4 activity is sustained which indicates that once-daily dosing is appropriate. Effective half-life for accumulation of drug is 12 hours when multiple oral doses of 5 mg are given.

Clearance

Renal clearance, steady state = 70 mL/min

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

Interactions

Drug Interactions
DrugInteraction
AbacavirThe serum concentration of Abacavir can be decreased when it is combined with Linagliptin.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Linagliptin.
AcetaminophenThe serum concentration of Linagliptin can be increased when it is combined with Acetaminophen.
AcetohexamideLinagliptin may increase the hypoglycemic activities of Acetohexamide.
Acetylsalicylic acidAcetylsalicylic acid may increase the hypoglycemic activities of Linagliptin.
AlbendazoleThe metabolism of Albendazole can be decreased when combined with Linagliptin.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Linagliptin.
AldosteroneThe serum concentration of Linagliptin can be decreased when it is combined with Aldosterone.
AlfuzosinThe metabolism of Alfuzosin can be decreased when combined with Linagliptin.
AlitretinoinThe serum concentration of Alitretinoin can be increased when it is combined with Linagliptin.
Food Interactions
  • Although a high fat meal reduces Cmax and increases AUC, this interaction with food is not clinically significant

References

Synthesis Reference

Pietro ALLEGRINI, Emanuele ATTOLINO, Marco ARTICO, "PROCESS FOR THE PREPARATION OF LINAGLIPTIN." U.S. Patent US20120165525, issued June 28, 2012.

US20120165525
General References
  1. Forst T, Pfutzner A: Linagliptin, a dipeptidyl peptidase-4 inhibitor with a unique pharmacological profile, and efficacy in a broad range of patients with type 2 diabetes. Expert Opin Pharmacother. 2012 Jan;13(1):101-10. doi: 10.1517/14656566.2012.642863. [PubMed:22149370]
External Links
KEGG Drug
D09566
PubChem Compound
10096344
PubChem Substance
175427132
ChemSpider
8271879
BindingDB
50228403
ChEBI
68610
ChEMBL
CHEMBL237500
HET
356
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Linagliptin
ATC Codes
A10BH05 — LinagliptinA10BD19 — Linagliptin and empagliflozinA10BD11 — Metformin and linagliptin
AHFS Codes
  • 68:20.05 — Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
PDB Entries
2rgu
FDA label
Download (353 KB)
MSDS
Download (104 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedHealth Services ResearchHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers31
1CompletedTreatmentHepatic Insufficiency1
1CompletedTreatmentType 2 Diabetes Mellitus3
1RecruitingOtherDiabetes Mellitus (DM) / High Blood Pressure (Hypertension)1
1RecruitingTreatmentHealthy Volunteers1
1TerminatedTreatmentSchizophrenic Disorders1
1, 2RecruitingTreatmentGastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma1
2CompletedTreatmentType 2 Diabetes Mellitus5
2Enrolling by InvitationTreatmentAlbuminuria / Impaired Renal Function / Type2 Diabetes Mellitus1
3Active Not RecruitingTreatmentLeft Ventricular Systolic Dysfunction / Type 2 Diabetes Mellitus1
3CompletedNot AvailableAlbuminuria / Arterial Hypertension1
3CompletedTreatmentType 2 DM Patients With Moderate or Severe Renal Impairment1
3CompletedTreatmentType 2 Diabetes Mellitus29
3Not Yet RecruitingTreatmentDM21
3RecruitingTreatmentType 2 Diabetes Mellitus3
3TerminatedTreatmentLeft Ventricular Diastolic Dysfunction / Type 2 Diabetes Mellitus1
3TerminatedTreatmentPlaque Morphology / Type 2 Diabetes Mellitus / Vascular Inflammation1
4Active Not RecruitingPreventionInsulin Resistance / Prediabetic State1
4Active Not RecruitingTreatmentType 2 Diabetes Mellitus1
4CompletedBasic ScienceType 2 Diabetes Mellitus2
4CompletedPreventionChronic Renal Failure (CRF) / Type 2 Diabetes Mellitus1
4CompletedTreatmentCoronary Artery Disease / Type 2 Diabetes Mellitus1
4CompletedTreatmentDiabetes Mellitus (DM)2
4CompletedTreatmentType 2 Diabetes Mellitus8
4CompletedTreatmentType2 Diabetes1
4Not Yet RecruitingTreatmentBone destruction / Diabetes Mellitus (DM)1
4Not Yet RecruitingTreatmentType 2 Diabetes Mellitus1
4RecruitingBasic ScienceSchizophrenic Disorders1
4RecruitingTreatmentImpaired Renal Function / Type 2 Diabetes Mellitus1
4RecruitingTreatmentKidney Transplant; Complications / New Onset Diabetes After Transplant1
4RecruitingTreatmentPeritoneal dialysis therapy / Type 2 Diabetes Mellitus1
4RecruitingTreatmentType II Diabetes in Subjects BMI 27 to 32 / Type II Diabetes in the Not so Obese1
4RecruitingTreatmentType2 Diabetes2
4RecruitingTreatmentType2 Diabetes Mellitus1
4TerminatedTreatmentType 2 Diabetes Mellitus1
4Unknown StatusBasic ScienceType 2 Diabetes Mellitus1
4Unknown StatusTreatmentInsulin Sensitivity/Resistance / Type 2 Diabetes Mellitus1
4Unknown StatusTreatmentType 2 Diabetes Mellitus1
4WithdrawnTreatmentAdvanced Glycation End Products / Diabetes Mellitus (DM) / SGLT-2 Inhibitors1
4WithdrawnTreatmentDiabetic Nephropathy Type 21
Not AvailableActive Not RecruitingBasic ScienceType 2 Diabetes Mellitus1
Not AvailableCompletedNot AvailableType 2 Diabetes Mellitus3
Not AvailableCompletedTreatmentChronic Kidney Disease (CKD) / Type 2 Diabetes Mellitus1
Not AvailableRecruitingNot AvailableDiabetes Mellitus (DM) / Kidney Function Affection Upon Exposure to Radiocontrast / Microalbuminuria1
Not AvailableRecruitingTreatmentDiabetes, Diabetes Mellitus Type 11
Not AvailableTerminatedNot AvailableType 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Tablet, film coated, extended releaseOral
Tablet, film coatedOral5 mg/1
TabletOral5 mg
Tablet, film coatedOral5 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2435730No2011-03-292022-02-21Canada
CA2496249No2012-01-242023-08-18Canada
US7407955No2003-08-122023-08-12Us
US6340475No1996-09-192016-09-19Us
US6635280No1996-09-192016-09-19Us
US6488962No2000-06-202020-06-20Us
US6303661No1997-04-242017-04-24Us
US6890898No1999-02-022019-02-02Us
US7078381No1999-02-022019-02-02Us
US7459428No1999-02-022019-02-02Us
US8119648No2003-08-122023-08-12Us
US8178541No2003-08-122023-08-12Us
US8846695No2010-06-042030-06-04Us
US9173859No2007-05-042027-05-04Us
US8853156No2011-03-052031-03-05Us
US8673927No2007-05-042027-05-04Us
US8883805No2005-11-262025-11-26Us
US9155705No2010-05-212030-05-21Us
US8551957No2009-10-192029-10-19Us
US7713938No2007-04-152027-04-15Us
US7579449No2005-11-052025-11-05Us
US9486526No2009-08-052029-08-05Us
US9415016No2009-04-022029-04-02Us
US9555001No2013-03-062033-03-06Us
US9949998No2014-06-112034-06-11Us
US10034877No2009-08-052029-08-05Us
US10022379No2009-04-022029-04-02Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<1 mg/mL MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.0502 mg/mLALOGPS
logP2.62ALOGPS
logP2.8ChemAxon
logS-4ALOGPS
pKa (Strongest Basic)9.86ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area113.48 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity133.43 m3·mol-1ChemAxon
Polarizability51.24 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9513
Caco-2 permeable-0.5842
P-glycoprotein substrateSubstrate0.774
P-glycoprotein inhibitor IInhibitor0.5185
P-glycoprotein inhibitor IINon-inhibitor0.7716
Renal organic cation transporterNon-inhibitor0.6658
CYP450 2C9 substrateNon-substrate0.803
CYP450 2D6 substrateNon-substrate0.7335
CYP450 3A4 substrateSubstrate0.7013
CYP450 1A2 substrateNon-inhibitor0.9273
CYP450 2C9 inhibitorNon-inhibitor0.8474
CYP450 2D6 inhibitorNon-inhibitor0.9176
CYP450 2C19 inhibitorNon-inhibitor0.8163
CYP450 3A4 inhibitorNon-inhibitor0.5548
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8562
Ames testNon AMES toxic0.5444
CarcinogenicityNon-carcinogens0.8587
BiodegradationNot ready biodegradable0.9966
Rat acute toxicity2.7553 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6109
hERG inhibition (predictor II)Inhibitor0.8116
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00di-0113900000-1cf1f79967a4761f3983
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0ufr-0391100000-8df1ebbcbdc456f86470
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00di-0114900000-928cf1c76b7fa52190f2

Taxonomy

Description
This compound belongs to the class of organic compounds known as xanthines. These are purine derivatives with a ketone group conjugated at carbons 2 and 6 of the purine moiety.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Imidazopyrimidines
Sub Class
Purines and purine derivatives
Direct Parent
Xanthines
Alternative Parents
Quinazolines / 6-oxopurines / Alkaloids and derivatives / Dialkylarylamines / Pyrimidones / Aminopiperidines / Aminoimidazoles / N-substituted imidazoles / Benzenoids / Vinylogous amides
show 9 more
Substituents
Xanthine / Diazanaphthalene / 6-oxopurine / Purinone / Quinazoline / Alkaloid or derivatives / Dialkylarylamine / 3-aminopiperidine / Pyrimidone / Piperidine
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aminopiperidine, quinazolines (CHEBI:68610)

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
References
  1. Forst T, Pfutzner A: Linagliptin, a dipeptidyl peptidase-4 inhibitor with a unique pharmacological profile, and efficacy in a broad range of patients with type 2 diabetes. Expert Opin Pharmacother. 2012 Jan;13(1):101-10. doi: 10.1517/14656566.2012.642863. [PubMed:22149370]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on May 21, 2013 16:46 / Updated on September 23, 2018 19:37