Sitagliptin Fenilalanil

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H24F6N6O2
Molecular Weight	554.4875
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)N2CCN3C(C2)=NN=C3C(F)(F)F)CC4=C(F)C=C(F)C(F)=C4

InChI

InChIKey=FFZDVHCAHYOEPA-UZLBHIALSA-N

InChI=1S/C25H24F6N6O2/c26-17-12-19(28)18(27)10-15(17)9-16(33-23(39)20(32)8-14-4-2-1-3-5-14)11-22(38)36-6-7-37-21(13-36)34-35-24(37)25(29,30)31/h1-5,10,12,16,20H,6-9,11,13,32H2,(H,33,39)/t16-,20+/m1/s1

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021995s034lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/23745054 https://www.ncbi.nlm.nih.gov/pubmed/17580730

Sitagliptin (MK-0431), chemically (2R)-4-Oxo-4-[3- (trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl]-1-(2,4,5-trifl uorophenyl)butan-2-amine has a very high selectivity towards DPP-4, with an IC(50) of 18 nM. There is no affinity towards other DDP enzymes (DPP- 8 and DPP-9). It has been approved for the treatment of type 2 diabetes in the USA and Europe and is registered by the name Januvia (Merck Pharmaceuticals, Whitehouse Station, NJ, USA). In healthy volunteers and in patients with type 2 diabetes of different ethnic background, the tolerability of different doses given once or twice daily is good. The drug works to competitively inhibit a protein/enzyme, dipeptidyl peptidase 4 (DPP-4), that results in an increased amount of active incretins (GLP-1 and GIP), reduced amount of release of glucagon (diminishes its release) and increased release of insulin. Sitagliptin is an incretin enhancer and the first marketed medication belonging to the gliptin class. In fact, no published literature exists regarding incidence or severity of hypoglycemia when sitagliptin is used off-label in combined with insulin therapy. However, is recommended to use methods to avoid hypoglycemia when using this off-label combination. Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dipeptidyl peptidase IV 37 Target ID: CHEMBL284 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17580730	Inhibitor 8297		18.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 259 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021995s034lbl.pdf	Palliative		Approved 8429	JANUVIA Approved Use JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1.1) Important Limitations of Use: •JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. (1.2) •JANUVIA has not been studied in patients with a history of pancreatitis. (1.2, 5.1) 1.1 Monotherapy and Combination Therapy JANUVIA® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. [See Clinical Studies (14). Launch Date 2006

C_max

Value	Dose	Co-administered	Analyte	Population
950 nM DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022044s046lbl.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		SITAGLIPTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
8.52 μM × h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022044s046lbl.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		SITAGLIPTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
12.4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022044s046lbl.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		SITAGLIPTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
62% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022044s046lbl.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		SITAGLIPTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/30346099	unhealthy, 14.8 years n = 8 Health Status: unhealthy Condition: type 2 diabetes mellitus Age Group: 14.8 years Sex: M+F Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/30346099	Other AEs: Vomiting... Other AEs: Vomiting (12.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/30346099
800 mg single, oral Studied dose Dose: 800 mg Route: oral Route: single Dose: 800 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021995lbl.pdf https://pubmed.ncbi.nlm.nih.gov/19602719	healthy, 18-45 years n = 77 Health Status: healthy Age Group: 18-45 years Sex: M+F Population Size: 77 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021995lbl.pdf https://pubmed.ncbi.nlm.nih.gov/19602719	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021995lbl.pdf https://pubmed.ncbi.nlm.nih.gov/19602719
1700 mg single, oral Overdose Dose: 1700 mg Route: oral Route: single Dose: 1700 mg Sources: https://pubmed.ncbi.nlm.nih.gov/22277726/	unknown, 86 years Health Status: unknown Age Group: 86 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/22277726/	Sources: https://pubmed.ncbi.nlm.nih.gov/22277726/

AEs

AE	Significance	Dose	Population
Vomiting	12.5%	200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/30346099	unhealthy, 14.8 years n = 8 Health Status: unhealthy Condition: type 2 diabetes mellitus Age Group: 14.8 years Sex: M+F Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/30346099

Overview

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

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OCT transporters 14 CYP 111 P-gp 1461 OAT3 642 CYP1A2 1524 CYP2B6 810 CYP2C8 911 CYP2C19 1478	CYP2C8 693 OAT3 339 P-gp 1537 OAT1 326 PEPT1 49 OCT2 355 OAT4 78

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15, 30	no [IC50 >100 uM]	no (co-administration study) Comment: results indicated that sitagliptin was not a time-dependent inhibitor of CYP3A4; sitagliptin did not meaningfully alter the pharmacokinetics of simvastatin. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15, 30
CYP 147	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022044s000_PharmR.pdf Page: 6.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022044s000_PharmR.pdf Page: 6.0	no
OCT transporters 14	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022044s000_ClinPharmR.pdf Page: 9.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no	no (co-administration study) Comment: sitagliptin had no inhibitory effect on the P-gp mediated transport of digoxin, verapmil, ritonavir, adn vinblastine Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0

Drug as victim

Target	Modality	Activity	Clinical evidence
OAT4 78	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	inconclusive
OAT1 326	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
OCT2 355	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
PEPT1 49	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 42	yes
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 42	yes
OAT3 339	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 15	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 15	yes	yes (co-administration study) Comment: cyclosporin A significantly inhibited P-gp transport of sitagliptin Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 15

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_PharmR.pdf Page: 22, 23

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:40237	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:40237
ChemicalBook	CB01449778	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB01449778
MolPort	MolPort-003-666-756	https://www.molport.com/shop/molecule-link/MolPort-003-666-756
ZINC	ZINC000001489478	http://zinc15.docking.org/substances/ZINC000001489478
eMolecules	6755163	https://www.emolecules.com/cgi-bin/more?vid=6755163

PubMed

Title	Date	PubMed
MK-431 (Merck).	2005 Apr	15898349
(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.	2005 Jan 13	15634008
New therapeutic strategies for the treatment of type 2 diabetes mellitus based on incretins.	2005 Summer	17491680
American Diabetes Association--66th scientific sessions. 9-13 June 2006, Washington, DC, USA.	2006 Aug	16871459
Dipeptidyl peptidase IV (DPP IV) inhibitors: A newly emerging drug class for the treatment of type 2 diabetes.	2006 Dec	17160910
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.	2006 Dec	17130197
Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes.	2006 Dec	17130196
Therapies for the treatment of type 2 diabetes mellitus based on incretin action.	2006 Jun	16682937
[Dipeptidylpeptidase IV inhibitors and dual action PPAR-agonists].	2006 Mar	16550882
DPP-4 inhibitors and their potential role in the management of type 2 diabetes.	2006 Nov	17073841
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.	2006 Oct	17157112
Oral agents for type 2 diabetes reduce HbA1c, are weight neutral.	2006 Sep	16998999
The burden of type 2 diabetes: strategies to prevent or delay onset.	2007	17969381
Review of sitagliptin phosphate: a novel treatment for type 2 diabetes.	2007	17580730
Sitagliptin: a viewpoint by Mark S. Kipnes.	2007	17352517
Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus.	2007 Apr	17940427
Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes.	2007 Apr	17407649
beta-cell failure in diabetes and preservation by clinical treatment.	2007 Apr	17353295
Characterization of two cyclic metabolites of sitagliptin.	2007 Apr	17220240
[Incretin enhancers, incretin mimetics: from therapeutic concept to clinical application].	2007 Apr 1	17383951
Type 2 diabetes drug boom: is newer better?	2007 Aug	17712909
Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus.	2007 Aug	17655515
Antidiabetic medications in overweight/obese patients with type 2 diabetes: drawbacks of current drugs and potential advantages of incretin-based treatment on body weight.	2007 Aug	17593274
Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors.	2007 Dec 15	17977724
Sitagliptin.	2007 Feb	17342863
Finding new treatments for diabetes--how many, how fast... how good?	2007 Feb 1	17267901
[New class of oral antidiabetic drugs. Effective in combination with metformin].	2007 Jan	17619359
Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes.	2007 Jan	17156104
Sitagliptin (Januvia) for type 2 diabetes.	2007 Jan 1	17179897
(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.	2007 Jan 1	17055272
New treatment for diabetes.	2007 Jan-Feb	17342826
The physiology of incretin hormones and the basis for DPP-4 inhibitors.	2007 Jan-Feb	17272793
A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies.	2007 Jul	17559747
[New concepts in the treatment of type 2 diabetes].	2007 Jul	17541529
Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes.	2007 Jun	17559733
Does addition of sitagliptin to metformin monotherapy improve glycemic control in patients with type 2 diabetes mellitus?	2007 Jun	17457306
Dipeptidyl peptidase-4 inhibitors: clinical data and clinical implications.	2007 Jun	17337494
Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drug.	2007 Mar	17300591
Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.	2007 Sep	17877544
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin.	2007 Sep	17593236
Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.	2007 Sep	17575559
Dose-proportionality of a final market image sitagliptin formulation, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.	2007 Sep	17571284
Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes.	2008 Feb	17933414
How lithium treatment generates neutrophilia by enhancing phosphorylation of GSK-3, increasing HIF-1 levels and how this path is important during engraftment.	2008 Jan	17906701
Dipeptidyl peptidase IV inhibitors and diabetes therapy.	2008 Jan 1	17981665

Patents

Sample Use Guides

In Vivo Use Guide

100 mg once daily. It can be taken with or without food.

Route of Administration: Oral

In Vitro Use Guide

Adipose tissue from adult-male Fischer 344 rats were cultured in endothelial progenitor cell culture medium for 14 d with (25 μmol/L) or without sitagliptin.

Name

Type

Language

Sitagliptin Fenilalanil

Official Name

English

(2S)-2-amino-N-{(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-yl}-3-phenylpropanamide

Systematic Name

English

(αS)-α-Amino-N-[(1R)-3-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-oxo-1-[(2,4,5-trifluorophenyl)methyl]propyl]benzenepropanamide

Systematic Name

English

Benzenepropanamide, α-amino-N-[(1R)-3-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-oxo-1-[(2,4,5-trifluorophenyl)methyl]propyl]-, (αS)-

Systematic Name

English

sitagliptin fenilalanil [INN]

Common Name

English

Code System Code Type Description

PUBCHEM

164886617