Linagliptin
[CAS# 668270-12-0]

Identification

• Classification: Pharmaceutical intermediate >> API intermediate
• Name: Linagliptin
• Synonyms: 8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione
• Molecular Formula: C₂₅H₂₈N₈O₂
• Molecular Weight: 472.54
• CAS Registry Number: 668270-12-0
• EC Number: 620-351-9
• SMILES: CC#CCN1C2=C(N=C1N3CCC[C@H](C3)N)N(C(=O)N(C2=O)CC4=NC5=CC=CC=C5C(=N4)C)C

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Melting point: 202 °C (Expl.)
• Boiling point: 661.2±65.0 °C 760 mmHg (Calc.)^*
• Flash point: 353.7±34.3 °C (Calc.)^*
• Solubility: DMSO: 17 mg/ml, Water: $lessThan$1 mg/ml (Expl.)
• Index of refraction: 1.717 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H332-H335
• Safety Statements: P280-P305+P351+P338-P310

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412

Discovery and Applications

Linagliptin is an oral antihyperglycemic agent belonging to the class of dipeptidyl peptidase-4 (DPP-4) inhibitors. It is used primarily in the management of type 2 diabetes mellitus to improve glycemic control. Chemically, linagliptin has the molecular formula C₂₅H₂₈N₈O₂, featuring a complex heterocyclic structure that includes a xanthine-based scaffold combined with a substituted purine moiety.

The mechanism of action of linagliptin involves selective inhibition of the DPP-4 enzyme, which is responsible for the degradation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By inhibiting DPP-4, linagliptin prolongs the activity of these incretins, enhancing glucose-dependent insulin secretion and suppressing glucagon release, leading to improved blood glucose regulation without causing hypoglycemia.

Linagliptin distinguishes itself from other DPP-4 inhibitors by its unique pharmacokinetic profile. It has a long terminal half-life, allowing once-daily dosing, and is predominantly eliminated via the enterohepatic system rather than renal excretion. This feature makes linagliptin particularly suitable for patients with varying degrees of renal impairment, as dosage adjustments are generally not required.

Synthetically, linagliptin is produced through multi-step chemical processes involving the construction of its bicyclic purine scaffold and the attachment of various substituents to optimize potency, selectivity, and pharmacokinetic properties. The drug is marketed as the free base or as its mesylate salt to enhance stability and solubility.

Clinically, linagliptin is prescribed as monotherapy or in combination with other antidiabetic agents such as metformin, sulfonylureas, or insulin. It effectively lowers fasting and postprandial blood glucose levels and has demonstrated a favorable safety profile, with minimal risk of weight gain or hypoglycemia.

Adverse effects associated with linagliptin are generally mild and may include nasopharyngitis, headache, and gastrointestinal symptoms. Rare cases of pancreatitis and hypersensitivity reactions have been reported, warranting monitoring during therapy.

In summary, linagliptin is a selective DPP-4 inhibitor used in type 2 diabetes management. Its chemical structure and pharmacological action enhance incretin hormone activity, improving glycemic control with a convenient dosing regimen and a safety profile suitable for patients with renal impairment.

References

2013. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet, 382(9902).
DOI: 10.1016/s0140-6736(13)61500-7

2017. Efficacy and Safety of Linagliptin in 2681 Asian Patients Stratified by Age, Obesity, and Renal Function: A Pooled Analysis of Randomized Clinical Trials. Advances in Therapy, 34(9).
DOI: 10.1007/s12325-017-0595-7

2019. Linagliptin protects rat carotid artery from balloon injury and activates the NRF2 antioxidant pathway. Experimental Animals, 68(1).
DOI: 10.1538/expanim.18-0089