Remibrutinib
[CAS# 1787294-07-8]

Identification

• Classification: Biochemical >> Inhibitor >> Angiogenesis >> BTK inhibitor
• Name: Remibrutinib
• Synonyms: N-[3-[6-amino-5-[2-[methyl(prop-2-enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2-fluorobenzamide
• Molecular Formula: C₂₇H₂₇F₂N₅O₃
• Molecular Weight: 507.53
• CAS Registry Number: 1787294-07-8
• SMILES: CC1=C(C=C(C=C1NC(=O)C2=C(C=C(C=C2)C3CC3)F)F)C4=C(C(=NC=N4)N)OCCN(C)C(=O)C=C

Properties

• Density: 1.3±0.1 g/cm³ Calc.^*
• Boiling point: 634.8±55.0 ºC 760 mmHg (Calc.)^*
• Flash point: 337.7±31.5 ºC (Calc.)^*
• Index of refraction: 1.633 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Danger
• Hazard Statements: H317-H334
• Precautionary Statements: P304+P341-P342+P311-P302+P352-P333+P313-P321-P261-P272-P280-P261-P285-P363-P501
• Transport Information: UN 2811

Discovory and Applicatios

Remibrutinib is a covalent Bruton’s tyrosine kinase (BTK) inhibitor developed to target B-cell and innate immune signaling pathways implicated in various inflammatory and autoimmune conditions. It was designed to bind covalently and selectively to the cysteine residue (Cys481) in the BTK active site, thereby achieving durable inhibition. The chemical structure of remibrutinib features a cyclopropylphenyl moiety and an aminopyrimidine core, which contribute to its high selectivity and pharmacological stability. Its development was driven by the need for more selective oral BTK inhibitors that minimize off-target effects while maintaining potent immunomodulatory action.

The compound emerged from a focused drug discovery program aimed at identifying small molecules capable of modulating BTK activity with a favorable pharmacokinetic and safety profile. BTK is a crucial component of the B-cell receptor (BCR) signaling pathway and is also involved in the activation of myeloid cells through Fc receptor signaling. Remibrutinib’s ability to irreversibly inhibit BTK makes it effective in downregulating these immune pathways, thereby reducing pathological immune responses in diseases characterized by immune dysregulation.

One of the primary therapeutic targets of remibrutinib is chronic spontaneous urticaria (CSU), a skin disorder characterized by persistent hives and angioedema without identifiable external triggers. In clinical development, remibrutinib has shown rapid and sustained symptom relief in CSU patients who are inadequately controlled by standard antihistamines. This outcome is achieved by reducing mast cell and basophil activation, which are mediated in part by BTK-dependent signaling pathways. The oral formulation of remibrutinib, combined with its favorable safety profile, makes it a promising treatment option for long-term management of CSU.

Remibrutinib is also being explored as a candidate for the treatment of multiple sclerosis (MS), an autoimmune disease characterized by demyelination and neuroinflammation in the central nervous system. Preclinical studies have demonstrated that BTK inhibition can reduce the activation of both peripheral B cells and central nervous system-resident microglia. In animal models of MS, remibrutinib was shown to suppress disease progression by attenuating inflammatory responses and preserving neural tissue integrity. These findings have provided the basis for ongoing clinical trials evaluating its efficacy in human MS patients.

In addition to CSU and MS, remibrutinib is under investigation for other immune-mediated conditions, including allergic diseases and systemic autoimmune disorders. Its highly selective binding reduces the risk of undesirable inhibition of kinases with structural similarity to BTK, which is a concern with less selective BTK inhibitors. Moreover, the irreversible nature of its binding leads to prolonged pharmacodynamic effects, allowing for twice-daily dosing while maintaining sustained therapeutic activity.

Safety evaluations of remibrutinib have indicated a low incidence of adverse effects, with the most common being headache, nasopharyngitis, and mild infections. Importantly, liver function and hematologic parameters remained within acceptable limits in long-term studies. This supports its use as a chronic treatment in conditions requiring continuous immune modulation. The compound's pharmacokinetics are characterized by rapid absorption, moderate bioavailability, and a half-life that supports its twice-daily regimen.

Remibrutinib represents a next-generation BTK inhibitor that builds on the therapeutic insights gained from earlier BTK-targeting agents. Its design and clinical profile position it as a leading candidate for the treatment of diseases where BTK plays a critical role in pathogenesis. Its continuing evaluation across multiple clinical indications reflects its potential to become an important addition to the therapeutic landscape for autoimmune and inflammatory diseases.

References

2020. Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton�s Tyrosine Kinase. Journal of Medicinal Chemistry, 63(5).
DOI: 10.1021/acs.jmedchem.9b01916

2022. Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria. The Journal of Allergy and Clinical Immunology, 150(6).
DOI: 10.1016/j.jaci.2022.08.027

2024. Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sj�gren�s syndrome: results from a randomised, double-blind, placebo-controlled phase 2 trial. Annals of the Rheumatic Diseases, 83(3).
DOI: 10.1136/ard-2023-224691