Deferasirox (Exjade^®, ICL670) Preclinical Overview

The availability of deferoxamine (DFO) in the 1960s represented a unique and significant advance in the treatment of iron-overloaded patients, dramatically improving patient prognosis and survival. The demanding treatment regimen, however, can limit long-term compliance with therapy with serious consequences. Efforts to identify appropriate oral therapy (at Novartis and its predecessor company) were largely unsuccessful (primarily due to toxicity issues) until the use of computational chemistry, and the development of a unique analytical model led to the development of a series of 40 bis-hydroxyphenyl-triazole based compounds and, ultimately, to the identification of deferasirox. Deferasirox is an achiral, tridentate ligand with a high affinity and selectivity for ferric iron (Fe³⁺). Acute and chronic dosing of deferasirox in animal models has demonstrated high efficiency, protracted duration of action, and dose-proportional effects of iron excretion with good tolerability.