Nintedanib
[CAS# 656247-17-5]

Identification

• Classification: API >> Respiratory medication >> Other respiratory medications
• Name: Nintedanib
• Synonyms: Vargatef; BIBF 1120; methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate
• Molecular Formula: C₃₁H₃₃N₅O₄
• Molecular Weight: 539.62
• CAS Registry Number: 656247-17-5
• EC Number: 809-588-0
• SMILES: CN1CCN(CC1)CC(=O)N(C)C2=CC=C(C=C2)N=C(C3=CC=CC=C3)C4=C(NC5=C4C=CC(=C5)C(=O)OC)O

Properties

• Density: 1.3±0.1 g/cm³ Calc.^*
• Boiling point: 742.2±60.0 °C 760 mmHg (Calc.)^*
• Flash point: 402.7±32.9 °C (Calc.)^*
• Solubility: DMSO 50 mg/mL, Water $lessThan$1 mg/mL (Expl.)
• Index of refraction: 1.658 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS05;GHS06;GHS08 Danger
• Risk Statements: H301-H315-H318-H361-H372
• Safety Statements: P201-P202-P260-P264-P270-P280-P301+P310+P330-P302+P352-P305+P351+P338+P310-P308+P313-P332+P313-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Acute toxicity	Acute Tox.	3	H301
Reproductive toxicity	Repr.	2	H361
Serious eye damage	Eye Dam.	1	H318
Reproductive toxicity	Repr.	1B	H360
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Eye irritation	Eye Irrit.	2	H319
Acute toxicity	Acute Tox.	4	H302
Eye irritation	Eye Irrit.	2A	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335

Discovery and Applications

Nintedanib is a small-molecule tyrosine kinase inhibitor that has gained prominence for its role in the treatment of idiopathic pulmonary fibrosis (IPF) and certain types of cancer, including non-small cell lung cancer (NSCLC). Chemically, nintedanib is a bisindolinone derivative that selectively targets multiple receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptors (VEGFR 1–3), platelet-derived growth factor receptors (PDGFR α and β), and fibroblast growth factor receptors (FGFR 1–3). Its discovery was part of efforts to develop multitargeted kinase inhibitors capable of interfering with signaling pathways involved in angiogenesis, fibrosis, and tumor progression.

The development of nintedanib began in the early 2000s through structure-based drug design strategies aimed at producing a potent, orally bioavailable inhibitor with high selectivity for angiogenic and fibrotic signaling pathways. Preclinical studies demonstrated that nintedanib effectively inhibits endothelial cell proliferation, fibroblast activation, and tumor growth in animal models. Its multitargeted mechanism of action allows simultaneous blockade of several signaling cascades, reducing redundancy and overcoming compensatory mechanisms often observed with single-target inhibitors.

Pharmacologically, nintedanib binds to the ATP-binding site of tyrosine kinases, preventing phosphorylation of downstream signaling molecules. In the context of idiopathic pulmonary fibrosis, this inhibition decreases fibroblast proliferation and extracellular matrix deposition, slowing the progression of lung fibrosis. In oncology applications, nintedanib inhibits tumor angiogenesis by blocking VEGFR-mediated signaling, thereby reducing tumor vascularization and growth. The compound is administered orally and exhibits moderate bioavailability, extensive tissue distribution, and metabolism primarily through esterases and cytochrome P450 enzymes, especially CYP3A4.

Clinically, nintedanib has been approved for the treatment of IPF, systemic sclerosis-associated interstitial lung disease, and as part of combination therapy for advanced NSCLC. In IPF, it has been shown to reduce the rate of decline in forced vital capacity, demonstrating significant efficacy in slowing disease progression. Its side effect profile is generally manageable, with gastrointestinal disturbances and liver enzyme elevations being the most common adverse events. The compound’s pharmacokinetics allow twice-daily dosing, and it can be combined with other antifibrotic or anticancer agents under careful monitoring.

From a chemical synthesis perspective, nintedanib is produced through a series of condensation, acylation, and cyclization reactions that construct the bisindolinone scaffold and introduce key substituents responsible for kinase binding. High-purity crystalline forms are obtained through careful control of reaction conditions, solvent selection, and purification processes. The final pharmaceutical formulation typically consists of oral capsules containing the active substance in combination with excipients to ensure stability, solubility, and bioavailability.

Nintedanib’s discovery and application exemplify the integration of medicinal chemistry, pharmacology, and clinical research in modern drug development. Its multitargeted kinase inhibition approach has expanded treatment options for fibrotic lung diseases and certain malignancies, while ongoing studies continue to explore its potential in additional therapeutic indications. The compound remains a benchmark for designing small-molecule inhibitors that target multiple disease-relevant pathways simultaneously.