molecular formula C25H28N8O2 B1675411 Linagliptin CAS No. 668270-12-0

Linagliptin

Katalognummer: B1675411
CAS-Nummer: 668270-12-0
Molekulargewicht: 472.5 g/mol
InChI-Schlüssel: LTXREWYXXSTFRX-QGZVFWFLSA-N
Achtung: Nur für Forschungszwecke. Nicht für den menschlichen oder tierärztlichen Gebrauch.
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Wirkmechanismus

Target of Action

Linagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) . DPP-4 is an enzyme responsible for the degradation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) . These hormones play a crucial role in regulating insulin secretion and glucose homeostasis .

Mode of Action

This compound works by inhibiting the DPP-4 enzyme, thereby slowing the inactivation of GLP-1 and GIP . This leads to an increase in the levels of these active incretins, which in turn enhances the production of insulin and decreases the production of glucagon by the pancreas . The result is a reduction in blood glucose levels in a glucose-dependent manner .

Biochemical Pathways

This compound’s administration leads to a decrease in the concentration of proinflammatory factors such as TNF-α, IL-6 and increases the number of anti-inflammatory patrolling monocytes . It also affects vascular dysfunction-related reactive oxygen species and inflammation, thus exhibiting anti-oxidative and anti-inflammatory properties . Moreover, this compound has been shown to have a positive effect on metabolic dysfunction and renal and/or cardiovascular damage .

Pharmacokinetics

This compound has a unique pharmacokinetic profile characterized by target-mediated nonlinear pharmacokinetics, concentration-dependent protein binding, minimal renal clearance, and no requirements for dose adjustment for any intrinsic or extrinsic factor . It is rapidly absorbed after oral administration, with maximum plasma concentration occurring after approximately 90 minutes, and reaches steady-state concentrations within 4 days . The majority of this compound is eliminated as the parent compound, demonstrating that metabolism plays a minor role in the overall pharmacokinetics in humans . This compound is eliminated primarily in feces, with only around 5% of the oral therapeutic dose excreted in the urine at steady state .

Result of Action

The inhibition of DPP-4 by this compound leads to increased levels of active incretins, which in turn stimulate the production of insulin and inhibit the production of glucagon . This results in a reduction of blood glucose levels in a glucose-dependent manner . Additionally, this compound has been shown to have neuroprotective properties, with potential effects on tissue repair and neuroprotection .

Action Environment

The efficacy of this compound can be influenced by various environmental factors. For instance, this compound’s pharmacokinetic profile allows it to be administered without any dose adjustment in conditions of renal impairment . Furthermore, this compound’s efficacy in improving glycemic control has been demonstrated in several different studies, both as a monotherapy and as an add-on therapy . .

Biochemische Analyse

Biochemical Properties

Linagliptin interacts with the enzyme DPP-4, inhibiting its activity . This inhibition slows the breakdown of incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), which play crucial roles in regulating insulin secretion and glucose homeostasis .

Cellular Effects

This compound has been shown to decrease the concentration of proinflammatory factors such as TNF-α, IL-6, and increase the number of anti-inflammatory patrolling monocytes CX3CR1 bright . It also improves vascular functions by increasing the production of nitric oxide (NO) and limiting the concentration of apolipoprotein B .

Molecular Mechanism

This compound is a competitive, reversible DPP-4 inhibitor . By inhibiting DPP-4, it slows the inactivation of GLP-1 and GIP, promoting blood glucose level reduction in a glucose-dependent manner .

Temporal Effects in Laboratory Settings

In clinical trials, this compound demonstrated efficacy in reducing glycated hemoglobin (HbA1c) levels in type 2 diabetes patients over time, while maintaining a placebo-like safety and tolerability profile .

Dosage Effects in Animal Models

In animal models of diabetes, this compound has shown significant reductions in plasma leptin levels and hepatic steatosis when administered at doses of 3 or 30 mg/kg .

Metabolic Pathways

This compound is involved in the incretin metabolic pathway. It inhibits the DPP-4 enzyme, slowing the breakdown of incretin hormones and thereby increasing their levels .

Transport and Distribution

This compound exhibits concentration-dependent protein binding in human plasma in vitro and has a large apparent volume of distribution, demonstrating extensive distribution into tissues .

Eigenschaften

IUPAC Name

8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

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
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI Key

LTXREWYXXSTFRX-QGZVFWFLSA-N
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Canonical SMILES

CC#CCN1C2=C(N=C1N3CCCC(C3)N)N(C(=O)N(C2=O)CC4=NC5=CC=CC=C5C(=N4)C)C
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Isomeric SMILES

CC#CCN1C2=C(N=C1N3CCC[C@H](C3)N)N(C(=O)N(C2=O)CC4=NC5=CC=CC=C5C(=N4)C)C
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Molecular Formula

C25H28N8O2
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

DSSTOX Substance ID

DTXSID201021653
Record name Linagliptin
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Description DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Molecular Weight

472.5 g/mol
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Solubility

<1 mg/mL, Soluble in methanol; sparingly soluble in ethanol; very slightly soluble in isopropanol, alcohol
Record name Linagliptin
Source DrugBank
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Record name Linagliptin
Source Hazardous Substances Data Bank (HSDB)
URL https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8204
Description The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel.

Mechanism of Action

Linagliptin is a competitive, reversible DPP-4 inhibitor. Inhibition of this enzyme slows the breakdown of GLP-1 and glucose-dependant insulinotropic polypeptide (GIP). GLP-1 and GIP stimulate the release of insulin from beta cells in the pancreas while inhibiting release of glucagon from pancreatic beta cells. These effects together reduce the breakdown of glycogen in the liver and increase insulin release in response to glucose., Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta-cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in a reduction in hepatic glucose output.
Record name Linagliptin
Source DrugBank
URL https://www.drugbank.ca/drugs/DB08882
Description The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
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Record name Linagliptin
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URL https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8204
Description The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel.

Color/Form

White to yellow solid; also reported as a crystalline solid

CAS No.

668270-12-0
Record name Linagliptin
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Description CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society.
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Record name Linagliptin [USAN:INN:JAN]
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Record name Linagliptin
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Record name Linagliptin
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Record name 8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2yl)methyl]purine-2,6-dione
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Record name LINAGLIPTIN
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Record name Linagliptin
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Description The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel.

Melting Point

190-196, 202 °C
Record name Linagliptin
Source DrugBank
URL https://www.drugbank.ca/drugs/DB08882
Description The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
Explanation Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
Record name Linagliptin
Source Hazardous Substances Data Bank (HSDB)
URL https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8204
Description The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel.

Retrosynthesis Analysis

AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.

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Strategy Settings

Precursor scoring Relevance Heuristic
Min. plausibility 0.01
Model Template_relevance
Template Set Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis
Top-N result to add to graph 6

Feasible Synthetic Routes

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Customer
Q & A

A: Linagliptin is a highly selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). [] This enzyme is responsible for the rapid degradation of incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). [, , ] By inhibiting DPP-4, this compound increases the levels of these incretin hormones, which in turn stimulate insulin secretion from pancreatic beta cells and suppress glucagon secretion from alpha cells, ultimately leading to improved glycemic control. [, , , ]

A: Research suggests that this compound can improve insulin sensitivity, particularly in the liver. Studies in diet-induced obese mice showed that long-term this compound treatment improved glucose disposal rates and suppressed hepatic glucose production during a euglycemic-hyperinsulinemic clamp, indicating enhanced insulin sensitivity. []

A: The molecular formula of this compound is C25H28N8O2, and its molecular weight is 472.54 g/mol. [, ]

A: While the provided abstracts don't delve into detailed spectroscopic analysis, they do mention techniques like X-ray crystallography being used to understand this compound's interaction with the DPP-4 enzyme. [] This technique helps visualize the drug's binding mode within the enzyme's active site.

ANone: The provided abstracts focus primarily on the pharmacological aspects of this compound and do not provide information on its material compatibility or stability in various conditions beyond standard pharmaceutical formulations.

ANone: this compound itself doesn't possess catalytic properties. Its action relies on inhibiting the catalytic activity of the DPP-4 enzyme.

A: While not explicitly detailed in the provided abstracts, computational chemistry techniques like QSAR (Quantitative Structure-Activity Relationship) are likely employed in the drug discovery and optimization process of this compound. [] These methods correlate structural features with biological activity, aiding in the design of more potent and selective DPP-4 inhibitors.

A: this compound is typically formulated as oral tablets for once-daily administration. [, , ] One study explored the bioequivalence of a fixed-dose combination tablet containing this compound, empagliflozin, and extended-release metformin compared to separate tablets, aiming to improve patient adherence. []

ANone: The provided abstracts primarily focus on preclinical and clinical research findings related to this compound and do not delve into specific SHE (Safety, Health, and Environment) regulations.

A: this compound demonstrates good oral absorption. [] Studies in rats using high-resolution autoradiography revealed that after intravenous administration, this compound-related radioactivity exhibited time- and dose-dependent localization in the kidneys, liver, and small intestine, reflecting the known distribution of DPP-4. [, ]

A: Unlike many other DPP-4 inhibitors primarily cleared by the kidneys, this compound is predominantly excreted via the enterohepatic system, with a small portion eliminated renally. [, ] This characteristic allows for its use without dose adjustment in patients with renal impairment. [, , ]

A: One study investigated the effect of food on this compound bioavailability when administered as a fixed-dose combination tablet with metformin. It concluded that food did not significantly impact this compound's bioavailability. []

A: Yes, in diet-induced obese mice, this compound significantly reduced liver fat content and improved glycemic control, as evidenced by lower blood glucose levels and improved glucose tolerance. [, ]

A: Numerous clinical trials have demonstrated that this compound effectively improves glycemic control in patients with type 2 diabetes. It significantly reduces HbA1c levels when used as monotherapy or in combination with other antidiabetic drugs. [, , , , , , , , ]

A: The CAROLINA trial, a large cardiovascular outcome trial, compared this compound to glimepiride (a sulfonylurea) in patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk. The results showed that this compound was non-inferior to glimepiride in reducing the risk of cardiovascular events. []

ANone: The provided abstracts don't specifically address resistance mechanisms to this compound or cross-resistance with other DPP-4 inhibitors or drug classes.

ANone: The provided abstracts focus primarily on oral administration of this compound and don't explore alternative drug delivery systems or targeting strategies.

ANone: The research presented in the abstracts doesn't specifically investigate biomarkers for predicting this compound efficacy, monitoring treatment response, or identifying potential adverse effects.

A: While not extensively discussed in the provided abstracts, high-performance liquid chromatography (HPLC) is a widely used technique for quantifying this compound in biological samples. [, ]

ANone: The ecological impact and degradation pathways of this compound aren't discussed in the provided research abstracts.

A: A dedicated study examined the impact of varying tablet dissolution characteristics on the bioavailability of this compound in a fixed-dose combination with metformin. It concluded that the observed differences in dissolution profiles did not significantly affect the bioavailability of either drug. []

ANone: While the provided research abstracts don't elaborate on specific analytical method validation details for this compound, it's crucial to adhere to established guidelines to ensure accuracy, precision, and specificity when quantifying this drug in various matrices.

ANone: The provided abstracts don't specifically address the immunogenicity potential of this compound or any immunological responses associated with its use.

A: Research indicates that this compound is a substrate for P-glycoprotein (P-gp), a drug efflux transporter. [, ] This interaction could potentially influence its absorption and distribution, particularly in organs with high P-gp expression, such as the intestine and brain. [, ]

ANone: The abstracts primarily focus on this compound's pharmacological properties and don't delve into its biocompatibility or biodegradability aspects.

ANone: The abstracts don't provide information related to the recycling or waste management of this compound.

A: The research abstracts highlight the use of various research tools and resources, including animal models like diabetic db/db mice and ZDF rats, cell-based assays using human U937 monocytes and brain microvascular endothelial cells, and clinical trials involving diverse patient populations. [, , , , ] These resources are essential for investigating this compound's efficacy and safety.

A: The approval of this compound by the US Food and Drug Administration on May 2, 2011, marked a significant milestone in the development of DPP-4 inhibitors for treating type 2 diabetes. [, ] This approval was based on a comprehensive clinical development program involving thousands of patients and demonstrating the drug's efficacy and safety profile.

A: The research on this compound highlights the importance of interdisciplinary collaboration, involving scientists from various fields such as pharmacology, endocrinology, cardiology, and medicinal chemistry. [, , , ] For instance, understanding this compound's effects on cardiovascular outcomes requires expertise from both cardiologists and endocrinologists. Similarly, developing and optimizing the drug's formulation and delivery systems necessitate contributions from pharmaceutical scientists.

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