Belumosudil API Manufacturers

General Description:

Belumosudil, identified by CAS number 911417-87-3, is a notable compound with significant therapeutic applications. Belumosudil is used in the treatment of chronic graft-versus-host disease (GVHD) and has been investigated for the treatment of pulmonary arterial hypertension. It is an inhibitor of rho-associated coiled-coil-containing protein kinases (ROCK), with significantly more selectivity for ROCK2 as compared to ROCK1 (IC₅₀ 100 nM vs. 3 μM, respectively). In the treatment of GVHD, a condition in which donor T-cells begin to attack recipient tissues following allogeneic hematopoeitic stem cell transplantation (HSCT), belumosudil helps to resolve immune dysregulation by shifting the balance between Th17 cells and T-regulatory cells, thereby dampening the inflammatory cascade that can occasionally be fatal. Belumosudil was first approved by the FDA in July 2021, under the brand name Rezurock, for the treatment of chronic GVHD in patients who have tried and failed at least two prior lines of systemic therapy. In July 2022, Belumosudil was approved by Health Canada under the brand name RHOLISTIQ to treat the same condition in adult and pediatric patients 12 years or older.

Indications:

This drug is primarily indicated for: Belumosudil is indicated for the treatment of chronic graft-versus-host disease (GVHD) in adult and pediatric patients 12 years of age and older following failure of at least two other lines of systemic therapy. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Belumosudil undergoes metabolic processing primarily in: The _in vitro_ metabolism of belumosudil occurs primarily via CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9. The specific metabolites generated by belumosudil metabolism remain unclear. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Belumosudil are crucial for its therapeutic efficacy: Following oral administration, the mean bioavailability of belumosudil is 64% and the median T_max at steady-state is 1.26 to 2.53 hours. As compared to administration in a fasted state, belumosudil C_max and AUC increased by 2.2 and 2 times, respectively, when administered with a high-fat, high-calorie meal. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Belumosudil is an important consideration for its dosing schedule: The mean elimination half-life of belumosudil following oral administration is 19 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Belumosudil exhibits a strong affinity for binding with plasma proteins: Belumosudil appears to be extensively protein-bound in plasma - _in vitro_ protein binding to serum albumin and alpha-1-acid glycoprotein was found to be 99.9% and 98.6%, respectively. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Belumosudil from the body primarily occurs through: Belumosudil is eliminated primarily in the feces. Following the administration of a radiolabeled oral dose of belumosudil in healthy subjects, approximately 85% of the radioactivity was recovered in the feces, 30% of which was unchanged parent drug, with less than 5% recovered in the urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Belumosudil is distributed throughout the body with a volume of distribution of: Following a single oral dose of belumosudil in healthy subjects, the mean geometric volume of distribution was 184 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Belumosudil is a critical factor in determining its safe and effective dosage: The mean clearance of belumosudil is 9.83 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Belumosudil exerts its therapeutic effects through: Belumosudil appears to inhibit several pro-fibrotic and pro-inflammatory processes in order to prevent and treat the damage incurred by graft-versus-host disease. Given its mechanism of action and findings in animal trials, belumosudil is considered to carry embryo-fetal toxicity and may cause significant harm to a developing fetus should a pregnant mother be exposed. Female patients of reproductive potential, or male patients with female partners of reproductive potential, should be advised to use effective contraception during treatment with belumosudil and for one week after the last dose. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Belumosudil functions by: Chronic graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation in which the transplanted donor T-cells recognize the recipient's tissues as foreign and mount an immune response. During the conditioning regimen prior to stem cell transplantation (e.g. involving irradiation or chemotherapy) the host tissues can become damaged which results in downstream inflammatory responses and the generation of inflammatory mediators like TNF-alpha and IL-1. These cytokines increase the expression of host major histocompatibility (MHC) antigens and adhesion molecules which enhances the ability of mature donor T-cells to recognize these molecules. The activation of these donor T-cells results in the activation of mononuclear phagocytes, whose effector functions are triggered by stimulatory molecules generated by the damage incurred during the conditioning phase of treatment. Activated macrophages and cytotoxic T-lymphocytes begin to directly lyse target cells and/or cause their apoptosis, which eventually leads to local tissue damage and further inflammatory responses. Belumosudil is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2), a protein that plays a vital role in the pathogenesis of immune and fibrotic diseases. The inhibition of ROCK2 has been shown to resolve immune dysregulation by down-regulating pro-inflammatory Th17 cells and up-regulating regulatory T-cells by manipulating the phosphorylation of STAT3 and STAT5. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Belumosudil is categorized under the following therapeutic classes: Acetates, Acids, Acyclic, Amides, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (strength unknown), Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 inhibitors (strength unknown), Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP2D6 Inhibitors, Cytochrome P-450 CYP2D6 Inhibitors (strength unknown), Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Enzyme Inhibitors, Heterocyclic Compounds, Fused-Ring, Immunosuppressive Agents, OATP1B1/SLCO1B1 Inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, Protein Kinase Inhibitors, Selective Immunosuppressants, UGT1A1 Inhibitors, UGT1A9 Inhibitors, UGT1A9 Substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Belumosudil include:

• Water Solubility: Practically insoluble
• Boiling Point: 682.6±55.0