Development of Tridentate Iron Chelators: From Desferrithiocin to ICL670

Abstract

Successful treatment of beta-thalassemia requires two key elements: blood transfusion and iron chelation. Regular blood transfusions considerably expand the lifespan of patients, however, without the removal of the consequential accumulation of body iron, few patients live beyond their second decade. In 1963, the introduction of desferrioxamine (DFO), a hexadentate chelator, marked a breakthrough in the treatment of beta-thalassemia. DFO significantly reduces body iron burden and iron-related morbidity and mortality. DFO is still the only drug for general use in the treatment of transfusion dependent iron overload. However, its very short plasma half-life and poor oral activity necessitate special modes of application (subcutaneous or intravenous infusion) which are inconvenient, can cause local reactions and are difficult to be accepted by many patients. Over the past four decades, many different laboratories have invested major efforts in the identification of orally active iron chelators from several hundreds of molecules of synthetic, microbial or plant origin. The discovery of ferrithiocin in 1980, followed by the synthesis of the tridentate chelator desferrithiocin and proof of its oral activity raised a lot of hope. However, the compound proved to be toxic in animals. Over a period of about fifteen years many desferrithiocin derivatives and molecules with broader alterations led to the discovery of numerous new compounds some of which were much better tolerated and were more efficacious than desferrithiocin in animals, however, none was safe enough to proceed to the clinical use. The discovery of a new chemical class of iron chelators: The bis-hydroxyphenyltriazoles re-energized the search for a safe tridentate chelator. The basic structure of this completely new chemical class of iron chelators was discovered by a combination of rational design, intuition and experience. More than forty derivatives of the triazole series were synthesized at Novartis. These compounds were evaluated, together with more than 700 chelators from various chemical classes. Using vigorous selection criteria with a focus on tolerability, the tridentate chelator 4-[(3,5-Bis-(2-hydroxyphenyl)-1,2,4)triazol-1-yl]-benzoic acid (ICL670) emerged as an entity which best combined high oral potency and tolerability in animals. ICL670 is presently being evaluated in the clinic.

Deferasirox in MDS patients with transfusion-caused iron overload—a phase-II study

“…The main toxic effects described were changes of renal tubular cells. The nephrotoxicity was regarded to be caused by decompartmentalization of chelated iron and had been observed in animals that were not heavily iron-overloaded [15]. Based on these observations, a creatinine clearance of <60 mL/ min was determined as an exclusion criterion for deferasirox treatment as recommended by the manufacturer.…”

“…Deferasirox binds iron in a 2:1 ratio before being excreted primarily in the bile [15]. A series of studies have demonstrated its efficacy and safety in patients with thalassemia major in a daily dose ranging between 20 and 30 mg/kg [12,[16][17][18][19][20][21].…”

Beta Thalassemia Major; Comparison of Deferasirox Versus Desferrioxamine as Iron Chelator in Multitransfused Patients

“…22 It is orally bioavailable and its terminal end half-life (t1/2) is somewhere around 8 and 16 hours, taking into consideration once-every day organization. Digestion system and end of deferasirox and the iron chelate (Fe-[deferasirox]2) is basically by glucuronidation took after by hepatobiliary discharge into the defecation.…”

Iron Chelation Therapy in Thalassemia Syndromes

“…Actually, Deferasirox is available in 90 nations. 34 Deferasirox, a N-substituted bis-hydroxyphenyltriazoles compound, belongs to a new class of tridentate iron chelators. It was selected among more than 700 molecules because it is orally administrable and it gave the best therapeutic results.…”

“…It was selected among more than 700 molecules because it is orally administrable and it gave the best therapeutic results. 34,35 Two molecules of Deferasirox are able to generate a stable complex with one molecule of iron. Its half life (t1/2) is between 8 and 16 hours, allowing a once-daily administration.…”