LINAGLIPTIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H28N8O2
Molecular Weight	472.5422
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC#CCN1C(=NC2=C1C(=O)N(CC3=NC4=CC=CC=C4C(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

HIDE SMILES / InChI

Description
Sources: https://investor.lilly.com/releasedetail2.cfm?ReleaseID=542971
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dipeptidyl peptidase IV 37 Target ID: CHEMBL284 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/201280s012lbl.pdf	Inhibitor 8297		1.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 259 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/201280s012lbl.pdf	Secondary		Approved 8429	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 2011

C_max

Value	Dose	Co-administered	Analyte	Population
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
8.9 nM DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf	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

Value	Dose	Co-administered	Analyte	Population
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
139 nM × h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf	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

T_1/2

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

F_unbound

Value	Dose	Co-administered	Analyte	Population
25% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf	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

Dose	Population	Adverse events
600 mg single, oral Highest studied dose Dose: 600 mg Route: oral Route: single Dose: 600 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf https://pubmed.ncbi.nlm.nih.gov/18812608	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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf https://pubmed.ncbi.nlm.nih.gov/18812608	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf https://pubmed.ncbi.nlm.nih.gov/18812608

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP2 4 OCT1 512 CYP2A6 707 CYP2E1 882 CYP4A11 21 CYP2C8 911 CYP1A2 1524 CYP2B6 810 CYP2C19 1478 P-gp 1461 BCRP 699 MRP2 383 OCT2 647 OAT4 146 OCTN1 29 OCTN2 66 OAT1 599 OAT3 642	P-gp 1537 BCRP 561 MRP2 205 OCT2 355 OAT4 78 OCTN1 47 OCTN2 50 OATP2 11 OCT1 327 OAT1 326 OAT3 339	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=201 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%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=201 Page: 38, (ClinPharm) 58, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 83-85, 201
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP4A11 25	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
BCRP 773	inhibitor 3277 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0	no
MRP2 475	inhibitor 3277 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT1 603	inhibitor 3277 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT3 644	inhibitor 3277 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT4 146	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OCTN2 71	inhibitor 3277 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OCT2 648	inhibitor 3277 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
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=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%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: 27, (ClinPharm) 58, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 92-93, 211
OCTN1 29	inhibitor 3277 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]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=58, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=204, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=210 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%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=58, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=204, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=210 Page: 38, (ClinPharm) 57, 58, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 86-87, 90-91, 204, 210
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=58, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=206 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%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=58, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=206 Page: 38, (ClinPharm) 57, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 88-89, 206-207
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=80 Page: 38, (PMDA in Japanese_I101-1) 80	yes [IC50 15 uM]	CD 1790 1
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=80 Page: 38, (PMDA in Japanese_I101-1) 80	yes [IC50 43.2 uM]	CD 1790 1
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=200 Page: 27, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 81-82, 200	yes [IC50 45.2 uM]
OATP2 4	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: 27, (PMDA in Japanese) 37, 38	yes [IC50 69.7 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=198, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=199 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%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=198, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=199 Page: 27, (ClinPharm) 58, 59, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 73-76, 77-80, 198, 199
BCRP 561	substrate 3367 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
MRP2 205	substrate 3367 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT1 326	substrate 3367 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT3 339	substrate 3367 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OATP2 11	substrate 3367 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OCT1 327	substrate 3367 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT4 78	substrate 3367 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
OCT2 355	substrate 3367 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
OCTN1 47	substrate 3367 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
OCTN2 50	substrate 3367 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=198, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=199 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%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=198, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=199 Page: 38, (ClinPharm) 58, 59, (PMDA in Japanese_K101-1) 73-76, 77-80, 198, 199

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33 Page: 27.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:68610	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:68610
ChemicalBook	CB71518518	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB71518518
MolPort	MolPort-021-783-260	https://www.molport.com/shop/molecule-link/MolPort-021-783-260
Selleck Chemicals	linagliptin-bi-1356	http://www.selleckchem.com/products/linagliptin-bi-1356.html
ZINC	ZINC000003820029	http://zinc15.docking.org/substances/ZINC000003820029

PubMed

Title	Date	PubMed
		252160946
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	18052023
(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	18223196
The centrosome protein NEDD1 as a potential pharmacological target to induce cell cycle arrest.	2009 Feb 25	19243593
Tissue distribution of the novel DPP-4 inhibitor BI 1356 is dominated by saturable binding to its target in rats.	2009 Jul	19562682
Binding to dipeptidyl peptidase-4 determines the disposition of linagliptin (BI 1356)--investigations in DPP-4 deficient and wildtype rats.	2009 Nov	19771584
Linagliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.	2009 Oct	19777398
Design, statistical analysis and sample size calculation of a phase IIb/III study of linagliptin versus voglibose and placebo.	2009 Sep 5	19732457
Incorrect description of mode of excretion of linagliptin.	2010	21701621
Dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: safety, tolerability, and efficacy.	2010	21701614
The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans.	2010 Apr	20086031
Pharmacokinetics and pharmacodynamics of single rising intravenous doses (0.5 mg-10 mg) and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) in healthy male subjects.	2010 Dec	21053992
Incretin concepts.	2010 Feb	20103551
Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type 2 diabetes.	2010 Jan	19947894
The evolving place of incretin-based therapies in type 2 diabetes.	2010 Jul	20130920
Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin.	2010 Jun	20497745
New treatments in the management of type 2 diabetes: a critical appraisal of saxagliptin.	2010 May 10	21437082
DPP-4 inhibitors: what may be the clinical differentiators?	2010 Nov	20708812
Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase-4 inhibitor linagliptin and pioglitazone in healthy volunteers.	2010 Oct	20875371
The dipeptidyl peptidase-4 inhibitor linagliptin exhibits time- and dose-dependent localization in kidney, liver, and intestine after intravenous dosing: results from high resolution autoradiography in rats.	2010 Sep	20538719
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	22149370

Patents

Sample Use Guides

In Vivo Use Guide

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

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

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

BI1356

Code

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

Linagliptin [WHO-DD]

Common 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