U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C25H28N8O2
Molecular Weight 472.5432
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LINAGLIPTIN

SMILES

CC#CCn1c2c(nc1N3CCC[C@]([H])(C3)N)n(C)c(=O)n(Cc4nc(C)c5ccccc5n4)c2=O

InChI

InChIKey=LTXREWYXXSTFRX-QGZVFWFLSA-N
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

HIDE SMILES / InChI

Description
Curator's Comment:: description was created based on several sources, including

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor discovered by Boehringer Ingelheim and being developed as an oral once-daily tablet for the treatment of Type 2 diabetes. Linagliptin was first approved by FDA in 2011 under the trade name Tradjenta as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Linagliptin binds to DPP-4 (an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4, and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

CNS Activity

Curator's Comment:: Linagliptin does not cross the blood brain barrier, and therefore its effects are peripheral rather than directly in the central nervous system.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
1.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Secondary
TRADJENTA

Approved Use

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Has not been studied in combination with insulin.

Launch Date

1.30429446E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
16.4 nM
5 mg 1 times / day steady-state, oral
dose: 5 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
LINAGLIPTIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
8.9 nM
5 mg single, oral
dose: 5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
LINAGLIPTIN plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
194 nM × h
5 mg 1 times / day steady-state, oral
dose: 5 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
LINAGLIPTIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
139 nM × h
5 mg single, oral
dose: 5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
LINAGLIPTIN plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
119 h
5 mg 1 times / day steady-state, oral
dose: 5 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
LINAGLIPTIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
25%
5 mg single, oral
dose: 5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
LINAGLIPTIN plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
600 mg single, oral
Highest studied dose
healthy, 38.3 years (range: 23-63 years)
n = 6
Health Status: healthy
Age Group: 38.3 years (range: 23-63 years)
Sex: M
Population Size: 6
Sources:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no [IC50 >10 uM]
no (co-administration study)
Comment: Pooled human liver microsomes (paclitaxel 6a-hydroxylation), Coadministration of linagliptin (10 mg QD days 1-12) decreased pioglitazone (CYP2C8 & CYP3A4 substrate, 45 mg QD days 6-12) AUCtau,ss by 5.6% and Cmax,ss by 14.4%.
Page: 38, (ClinPharm) 58, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 83-85, 201
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no
no
no
no
no
no
no
no
no
no
no (co-administration study)
Comment: OCT2-HEK293 cells, Coadministration of linagliptin increased metformin (OCT2 substrate) AUCtau,ss by 0.8% and decreased Cmax,ss by 11.4%.
Page: (ClinPharm) 59, (PMDA in Japanese) 37, 38
weak [IC50 66.1 uM]
unlikely (co-administration study)
Comment: MDR1-LLC-PK cells, MDR1-MDCKII cell monolayers; IC50 = 55 mcM (Caco-2 cells), concentration dependent and saturable inhibitor, Coadministration of ligagliptin increased Digoxin (P-gp substrate) AUCtau,ss by 1.5% and decreased Cmax by 5.8%.
Page: 27, (ClinPharm) 58, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 92-93, 211
weak [IC50 >100 uM]
weak [IC50 >100 uM]
unlikely (co-administration study)
Comment: Pooled human liver microsomes (tolbutamide hydroxylation); IC50 = 19.6 mcM (diclofenac 4'-hydroxylation); IC50 = 15.2 mcM, Ki = 8.28 mcM (flurbiprofen 4'-hydroxylation); Coadministration of linagliptin decreased R-warfarin (warfarin, CYP2C9 substrate) AUC0-inf by 1.5% and Cmax 0.3%, and increased S-warfarin AUC0-inf by 3.0% and Cmax by 0.9%. Coadministration of linagliptin decreased glyburide (CYP2C9 substrate) AUC0-inf by 14.3% and Cmax by 13.8%.
Page: 38, (ClinPharm) 57, 58, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 86-87, 90-91, 204, 210
weak [Ki 36.3 uM]
weak (co-administration study)
Comment: Pooled human liver microsomes (testosterone 6b-hydroxylation, IC50 = 36.3 mcM, Ki = 115 mcM; erythromycin N-demethylation, IC50 = 41.6 mcM), irreversible inhibitior (poor to moderate); Due to the high potency DPP4 inhibition of linagliptin, resulting in clinical Cmax of 20 nM, the potential for in vivo CYP3A4, MAO-B, or CYP2C9 inhibition are minimal at therapeutic exposures. Coadministration of linagliptin increased simvastatin (CYP3A4 substarate) AUCtau,ss by 34.17% and Cmax,ss by 10.01%, and simvastatin acid AUCtau,ss by 33.26% and Cmax,ss by 20.74%.
Page: 38, (ClinPharm) 57, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 88-89, 206-207
yes [IC50 15 uM]
yes [IC50 43.2 uM]
yes [IC50 45.2 uM]
yes [IC50 69.7 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
moderate [Km 187 uM]
yes (co-administration study)
Comment: MDR1-LLC-PK cells, MDR1-MDCKII cell monolayers, Coadministration of ritonavir (potent P-gp and CYP3A4 inhibitor) increased linagliptin AUC0-24 by 101.4% and Cmax by 195.7%., Coadministration of rifampicin (potent P-gp and CYP3A4 inducer) decreased linagliptin AUCtau,ss by 39.5% and Cmax,ss by 43.8%.
Page: 27, (ClinPharm) 58, 59, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 73-76, 77-80, 198, 199
no
no
no
no
no
no
yes
yes
yes
yes
yes
yes (co-administration study)
Comment: Coadministration of ritonavir (potent P-gp and CYP3A4 inhibitor) increased linagliptin AUC0-24 by 101.4% and Cmax by 195.7%., Coadministration of rifampicin (potent P-gp and CYP3A4 inducer) decreased linagliptin AUCtau,ss by 39.5% and Cmax,ss by 43.8%.
Page: 38, (ClinPharm) 58, 59, (PMDA in Japanese_K101-1) 73-76, 77-80, 198, 199
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.
2007 Dec 27
(R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors.
2008 Apr
3,5-Dihydro-imidazo[4,5-d]pyridazin-4-ones: a class of potent DPP-4 inhibitors.
2008 Jun 1
Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers.
2008 Oct
Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients.
2009 Aug
Chronic treatment with the dipeptidyl peptidase-4 inhibitor BI 1356 [(R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] increases basal glucagon-like peptide-1 and improves glycemic control in diabetic rodent models.
2009 Feb
The centrosome protein NEDD1 as a potential pharmacological target to induce cell cycle arrest.
2009 Feb 25
Inhibition of dipeptidyl peptidase 4 by BI-1356, a new drug for the treatment of beta-cell failure in type 2 diabetes.
2009 Jun
Binding to dipeptidyl peptidase-4 determines the disposition of linagliptin (BI 1356)--investigations in DPP-4 deficient and wildtype rats.
2009 Nov
Linagliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.
2009 Oct
Design, statistical analysis and sample size calculation of a phase IIb/III study of linagliptin versus voglibose and placebo.
2009 Sep 5
Incorrect description of mode of excretion of linagliptin.
2010
Dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: safety, tolerability, and efficacy.
2010
The evolving place of incretin-based therapies in type 2 diabetes.
2010 Jul
Type 2 diabetes: postprandial hyperglycemia and increased cardiovascular risk.
2010 Mar 24
New treatments in the management of type 2 diabetes: a critical appraisal of saxagliptin.
2010 May 10
DPP-4 inhibitors: what may be the clinical differentiators?
2010 Nov
Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy.
2011
Linagliptin, a dipeptidyl peptidase-4 inhibitor with a unique pharmacological profile, and efficacy in a broad range of patients with type 2 diabetes.
2012 Jan
Patents

Sample Use Guides

The recommended dose of Tradjenta is 5 mg once daily, tablets can be taken with or without food.
Route of Administration: Oral
To study dissociation of BI 1356 (linagliptin) from the DPP-4 enzyme Caco-2 cell extract was preincubated with BI 1356 at concentration of 30 nM for, high above the respective Ki value of 1 nM. The enzymatic reaction was started by adding the substrate after a 3000-fold dilution of the preincubation mixture. Enzyme rates in the presence of BI 1356 were measured at different times after dilution (v in relative fluorescence units/seconds × 1000) and corrected for the rate of an uninhibited reaction. koff rate was obtained from a one-phase exponential decay equation fitted to the data points. The calculated koff rate for BI 1356 was 3.0 × 10(–5)/s.
Name Type Language
LINAGLIPTIN
DASH   INN   JAN   MART.   MI   ORANGE BOOK   USAN   VANDF   WHO-DD  
USAN   INN  
Official Name English
TRIJARDY XR COMPONENT LINAGLIPTIN
Brand Name English
LINAGLIPTIN [INN]
Common Name English
GLYXAMBI COMPONENT LINAGLIPTIN
Brand Name English
BI-1356
Code English
8-((3R)-3-AMINOPIPERIDIN-1-YL)-7-(BUT-2-YN-1-YL)-3-METHYL-1-((4-METHYLQUINAZOLIN-2-YL)METHYL)-3,7-DIHYDRO-1H-PURINE-2,6-DIONE
Systematic Name English
LINAGLIPTIN [VANDF]
Common Name English
(R)-8-(3-AMINO-PIPERIDIN-1-YL)-7-BUT-2-YNYL-3-METHYL-1-(4-METHYL-QUINAZOLIN-2-YLMETHYL)-3,7-DIHYDRO-PURINE-2,6-DIONE
Systematic Name English
LINAGLIPTIN COMPONENT OF JENTADUETO
Common Name English
BS-1356-BS
Code English
LINAGLIPTIN [WHO-DD]
Common Name English
1H-PURINE-2,6-DIONE, 8-((3R)-3-AMINO-1-PIPERIDINYL)-7-(2-BUTYNYL)-3,7-DIHYDRO-3-METHYL-1-((4-METHYL-2- QUINAZOLINYL)METHYL)-
Systematic Name English
TRAZENTA
Brand Name English
LINAGLIPTIN [MI]
Common Name English
LINAGLIPTIN COMPONENT OF TRIJARDY XR
Brand Name English
LINAGLIPTIN [USAN]
Common Name English
BI-1356-BS
Code English
LINAGLIPTIN [JAN]
Common Name English
LINAGLIPTIN [ORANGE BOOK]
Common Name English
BI-1356BS
Code English
BI 1356
Code English
TRAJENTA
Brand Name English
BI 1356 BS
Code English
LINAGLIPTIN [MART.]
Common Name English
LINAGLIPTIN COMPONENT OF GLYXAMBI
Brand Name English
JENTADUETO COMPONENT OF LINAGLIPTIN
Common Name English
BS 1356 BS
Code English
Classification Tree Code System Code
NCI_THESAURUS C98086
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
WHO-ATC A10BD11
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
WHO-VATC QA10BH05
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
WHO-ATC A10BD19
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
LIVERTOX 558
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
WHO-VATC QA10BD11
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
WHO-ATC A10BH05
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
NDF-RT N0000175913
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
Code System Code Type Description
HSDB
8204
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
MERCK INDEX
M6819
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PRIMARY Merck Index
IUPHAR
6318
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
DRUG BANK
DB08882
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
EVMPD
SUB31340
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
PUBCHEM
10096344
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
MESH
C568794
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
DRUG CENTRAL
4175
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
INN
9039
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PRIMARY
RXCUI
1100699
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY RxNorm
ChEMBL
CHEMBL237500
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
LACTMED
Linagliptin
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
WIKIPEDIA
LINAGLIPTIN
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
CAS
668270-12-0
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
FDA UNII
3X29ZEJ4R2
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY
NCI_THESAURUS
C83887
Created by admin on Fri Jun 25 20:34:05 UTC 2021 , Edited by admin on Fri Jun 25 20:34:05 UTC 2021
PRIMARY