Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-3
A Hydrogen Peroxide Sensitive Prodrug Strategy for the Targeted Delivery of Methotrexate in Rheumatoid Arthritis
Systemic exposure to methotrexate, an anti-inflammatory and immunomodulating drug, is associated with haematological, gastrointestinal, and lung toxicity. A targeted drug delivery in tissues affected by inflammation might retain therapeutic efficacy whilst preventing exposure to normal organs and tissues. Peiró Cadahía et al. investigated a methotrexate prodrug strategy consisting of a reactive oxygen species-labile 4-methylphenylboronic acid linked to methotrexate via a carbamate linkage, that led to the synthesis of a novel prodrug, (4-(((2-amino-4-((((4-boronobenzyl)oxy) carbonyl)amino)pteridin-6-yl)methyl)(methyl)amino)benzoyl)-L-glutamic acid [1]. Incubation of this prodrug with reactive oxygen species, at concentrations similar to those observed in inflammatory tissues, led to the exclusive release of methotrexate. In an animal model of inflammatory arthritis, this prodrug significantly reduced the macroscopic arthritis score when compared to the control group. The effect of the prodrug on the arthritis score was similar to that observed with methotrexate. Notably, progressive weight loss, a marker of toxicity, was observed with methotrexate, but not with the prodrug. A hydrogen peroxide sensitive prodrug strategy for the targeted delivery of methotrexate is a novel, promising, approach for the treatment of patients with rheumatoid arthritis.
