Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C25H28N8O2 |
Molecular Weight | 472.5422 |
Optical Activity | ( - ) |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC#CCN1C(=NC2=C1C(=O)N(CC3=NC4=C(C=CC=C4)C(C)=N3)C(=O)N2C)N5CCC[C@@H](N)C5
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
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=23520281
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.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL284 |
1.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Secondary | TRADJENTA Approved UseIndicated 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 Date2011 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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 |
|
16.4 nM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23331248 |
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 |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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 |
|
194 nM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23331248 |
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 |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
119 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23331248 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 38, (ClinPharm) 58, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 83-85, 201 |
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 |
||
Page: 38, (PMDA in Japanese) 78 |
no [IC50 >100 uM] | |||
Page: 38, (PMDA in Japanese) 78 |
no [IC50 >100 uM] | |||
Page: 38, (PMDA in Japanese) 78 |
no [IC50 >100 uM] | |||
Page: 38, (PMDA in Japanese) 78 |
no [IC50 >100 uM] | |||
Page: 38, (PMDA in Japanese) 78 |
no [IC50 >100 uM] | |||
Page: 38, (PMDA in Japanese) 78 |
no [IC50 >100 uM] | |||
Page: 38, (PMDA in Japanese) 78 |
no [IC50 >100 uM] | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0 |
no | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0 |
no | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
no | ||||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (ClinPharm) 59, (PMDA in Japanese) 37, 38 |
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%. Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (ClinPharm) 59, (PMDA in Japanese) 37, 38 |
||
Page: 27, (ClinPharm) 58, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 92-93, 211 |
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 |
||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38 |
weak [IC50 >100 uM] | |||
Page: 38, (ClinPharm) 57, 58, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 86-87, 90-91, 204, 210 |
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 |
||
Page: 38, (ClinPharm) 57, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 88-89, 206-207 |
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 |
||
Page: 38, (PMDA in Japanese_I101-1) 80 |
yes [IC50 15 uM] | |||
Page: 38, (PMDA in Japanese_I101-1) 80 |
yes [IC50 43.2 uM] | |||
Page: 27, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 81-82, 200 |
yes [IC50 45.2 uM] | |||
Page: 27, (PMDA in Japanese) 37, 38 |
yes [IC50 69.7 uM] |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 27, (ClinPharm) 58, 59, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 73-76, 77-80, 198, 199 |
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 |
||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38 |
no | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38 |
yes | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38 |
yes | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38 |
yes | |||
Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38 |
yes | |||
Page: 38, (ClinPharm) 58, 59, (PMDA in Japanese_K101-1) 73-76, 77-80, 198, 199 |
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
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33 Page: 27.0 |
PubMed
Title | Date | PubMed |
---|---|---|
Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. | 2009 Aug |
|
Tissue distribution of the novel DPP-4 inhibitor BI 1356 is dominated by saturable binding to its target in rats. | 2009 Jul |
|
Inhibition of dipeptidyl peptidase 4 by BI-1356, a new drug for the treatment of beta-cell failure in type 2 diabetes. | 2009 Jun |
|
Linagliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. | 2009 Oct |
|
Incorrect description of mode of excretion of linagliptin. | 2010 |
|
The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. | 2010 Apr |
|
Impact of target-mediated drug disposition on Linagliptin pharmacokinetics and DPP-4 inhibition in type 2 diabetic patients. | 2010 Aug |
|
Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. | 2010 Dec |
|
Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin. | 2010 Jun |
|
Type 2 diabetes: postprandial hyperglycemia and increased cardiovascular risk. | 2010 Mar 24 |
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
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=18223196
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.
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ACTIVE MOIETY