Promising prodrug candidates for safe and efficient treatment of Rheumatoid Arthritis (RA) are presented.
Rheumatoid Arthritis (RA) is an autoimmune disease and chronic inflammatory disorder associated with progressive disability and reduced life time expectancy. Affecting around 1% of the world’s population, RA has large socio-economic costs. The project presents new prodrug candidates for RA treatment.
RA is characterized by synovial inflammation and tissue damage. The origin and cause are unknown, and no cure exists. However, treatments that reduce the symptoms and the activity of the disease have appeared over the last three decades. The standard of care treatment is by disease-modifying anti-rheumatic drugs (DMARDs), where methotrexate (MTX) is the frontline drug.
A characteristic of the inflammatory tissue associated with RA is known as oxidative stress. A number of reactive oxygen species (ROS) are found, e.g. hydrogen peroxide (H2O2), in up to 100-fold increase when compared to healthy tissue. As ROS are cytotoxic to invading bacteria, they are a cornerstone in the human immune system. However, sustained elevated ROS levels unrelated to infections are harmful, and it is an obvious ambition to reduce the oxidative stress in RA patients.
In the project, novel H2O2-sensitive prodrugs of MTX and the related aminoptherin (AMT) were synthesized. The strategy was based on H2O2-triggered pro-moieties attached to the drugs via
different linkers. Proof-of-principle was achieved, as in vitro activation of the prodrugs proved to be effective under pathologic concentrations of H2O2 reported for inflammatory tissues.
The solubility and chemical stability of the synthesized prodrugs were evaluated. Further, selected candidates were assessed in pharmacokinetic assays. The prodrug candidates showed moderate to good solubility, high chemical and enzymatic stability, and biological activity comparable to that of
the parent drugs. Additionally, the in vivo efficacy and preliminary toxicity in the type-II collagen-induced arthritis murine model were assessed, verifying the potential use of the prodrug candidates in RA therapy.
In a separate part of the project, a novel methodology for selective activation of classically unreactive methyl-C(sp3)-H bonds in aliphatic amines was developed. A diverse range of substrates were able to undergo unprecedented regioselective methyl-C(sp3)-H carbonylation, forming the corresponding γ-lactams in good yields and high diastereoselectivities under optimized reaction conditions.
In conclusion, a site-selective H2O2-sensitive prodrug strategy has been applied to MTX and AMT, and data was collected to prove the potential use of the prodrug candidates for a safer and efficient treatment of RA when compared to the parent drugs, showing very promising results, which encourage further studies.
Illustration:
The innate immune system is constituted of soluble factors and distinct cellular components including granulocytes (neutrophils, eosinophils, and basophils), mast cells, macrophages, natural killer cells, and dendritic cells. The adaptive immune system consists of B-cells, T-cells (T-helper or CD4+ and T-cytotoxic or CD8+), and antibodies.