Iptacopan
[CAS# 1644670-37-0]

Identification

• Classification: API >> Immune function drug >> Immunosuppressive drug
• Name: Iptacopan
• Synonyms: 4-[(2S,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid
• Molecular Formula: C₂₅H₃₀N₂O₄
• Molecular Weight: 422.52
• CAS Registry Number: 1644670-37-0
• SMILES: CCO[C@H]1CCN([C@@H](C1)C2=CC=C(C=C2)C(=O)O)CC3=C(C=C(C4=C3C=CN4)C)OC

Properties

• Density: 1.3±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.637, Calc.^*
• Boiling Point: 599.1±50.0 ºC (760 mmHg), Calc.^*
• Flash Point: 316.1±30.1 ºC, Calc.^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H315-H319
• Precautionary Statements: P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313

Discovory and Applicatios

Iptacopan is an orally administered small-molecule compound developed as a selective inhibitor of factor B, a key enzyme in the alternative pathway of the complement system. The complement system is a crucial part of innate immunity, consisting of a cascade of proteins that enhance the ability of antibodies and phagocytic cells to clear pathogens. Among the three major complement activation pathways—classical, lectin, and alternative—the alternative pathway functions both independently and as an amplification loop for the others. Factor B plays a central role in this pathway by participating in the formation of the C3 and C5 convertases, which are essential for the downstream inflammatory and cell-lytic responses mediated by complement activation.

The development of iptacopan was guided by the need to treat diseases characterized by dysregulation of the alternative complement pathway. These include rare hematologic and renal diseases such as paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), and atypical hemolytic uremic syndrome (aHUS). Prior to the emergence of iptacopan, most complement inhibitors targeted the terminal components of the cascade, such as C5. However, upstream inhibition at the level of factor B was proposed to allow a more complete and specific suppression of the alternative pathway, while potentially preserving host defense mechanisms mediated by the classical and lectin pathways.

Iptacopan binds to factor B and prevents its participation in the formation of the alternative pathway C3 convertase (C3bBb). This action blocks the cleavage of C3 into C3a and C3b, thereby halting the positive feedback loop of alternative pathway amplification. Inhibition at this stage also prevents the generation of C5 convertase and subsequent formation of the membrane attack complex, mitigating downstream inflammatory and cytolytic effects.

The pharmacological properties of iptacopan have enabled its investigation in several clinical contexts. In PNH, a disease in which red blood cells are destroyed by uncontrolled complement activation, iptacopan has shown potential to reduce intravascular hemolysis and improve hemoglobin levels, especially in patients with residual anemia despite terminal pathway inhibition. Its oral administration offers an alternative to existing injectable therapies, contributing to greater patient convenience and compliance.

In renal diseases such as C3G and aHUS, excessive alternative pathway activity leads to glomerular inflammation and damage. Iptacopan’s ability to modulate complement activation at the level of C3 convertase offers a targeted approach to control the underlying disease process. In these indications, studies have aimed to evaluate its impact on proteinuria, kidney function, and complement deposition in renal tissue.

Iptacopan’s selectivity for factor B has been critical to its safety profile, as it allows for pathway-specific inhibition while minimizing interference with the classical and lectin pathways. This distinction is particularly relevant in the context of host defense, where preservation of immune surveillance is desirable. The compound’s oral bioavailability and pharmacokinetics have supported once- or twice-daily dosing regimens, further enhancing its applicability in chronic disease management.

Beyond rare complement-mediated disorders, iptacopan is also being explored in other conditions involving complement dysregulation, though its use remains focused on indications with a clearly defined role for the alternative pathway. Its mechanism of action makes it an important tool in expanding the therapeutic landscape of complement inhibition, providing a new strategy for modulating immune responses with precision.

The discovery and application of iptacopan mark a significant advancement in the field of complement biology and therapeutics. By targeting an upstream component of the alternative pathway with high specificity, iptacopan provides new possibilities for disease control in patients with complement-driven pathology.

References

2019. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proceedings of the National Academy of Sciences of the United States of America, 116(16).
DOI: 10.1073/pnas.1820892116

2020. Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor. Journal of Medicinal Chemistry, 63(10).
DOI: 10.1021/acs.jmedchem.9b01870

2024. Iptacopan for the treatment of paroxysmal nocturnal hemoglobinuria. Expert Opinion on Pharmacotherapy, 25(14).
DOI: 10.1080/14656566.2024.2404110