PCTH: A Novel Orally Active Chelator for the Treatment of Iron Overload Disease

Abstract

Our laboratories have prepared a novel class of iron (Fe) chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) class. This article will review the iron chelation efficacy of this series of chelators, both in cell culture and in animal models. Several PCIH analogs were shown to be effective at inducing iron mobilization and preventing iron uptake from the iron-transport protein, transferrin. Moreover, several of these ligands were effective at permeating the mitochondrion and inducing iron release. Studies in mice demonstrated that the PCIH analog, PCTH, was orally active and well tolerated by mice at doses ranging from 50 to 100 mg kg⁻¹, twice daily (b.d.). A dose-dependent increase in fecal ⁵⁹Fe excretion was observed in the PCTH-treated group. This level of iron excretion was similar to that found for the orally effective chelators, pyridoxal isonicotinoyl hydrazone (PIH) and deferiprone (L1). The PCIH group of ligands clearly has the potential for the treatment of β-thalassemia (thal) and Friedreich's Ataxia (FA).

Keywords:

• Desferrioxamine (DFO)
• Iron (Fe)
• Iron chelators
• PCTH
• Pyridoxal isonicotinoyl hydrazone (PIH)

Notes

15. Richardson DR, Bernhardt P, Becker E. Iron Chelators and Uses Thereof. International Publication No. WO 01/17530, 2000