Rene Lattmann

Development of Tridentate Iron Chelators: From Desferrithiocin to ICL670

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.

4‐[3,5‐Bis(2‐hydroxyphenyl)‐1,2,4‐triazol‐1‐yl]‐ benzoic Acid: A Novel Efficient and Selective Iron(III) Complexing Agent

An exceptionally stable 1:2 complex [FeL2]3− is formed from the ligand H3L and FeIII. In contrast, the affinity of this ligand for other biometals is relatively small. These properties make H3L a highly promising candidate for medical applications (e.g. for the treatment of iron overload).

Valsartan, a potent, orally active angiotensin II antagonist developed from the structurally new amino acid series

Abstract Starting from the structure of DuP-753 and a 3-dimensional model of the pentapeptide Tyr-Ile-His-Pro-Ile, a series of new and highly potent antagonists has been designed where the imidazole moiety of the Du Pont compound has been replaced by an N-acylated aminoacid residue. VALSARTAN (Ex. 4e CGP48933, (S)-N-Valeryl-N-[2′-(1H-tetrazol-5-yl-)biphenyl-4-yl]methyl-valine), has been selected for clinical investigation.

ICL670A: Preclinical Profile

Man is unable to actively eliminate iron from the body, once it has been acquired. Toxic and eventually lethal levels of iron accumulate as a result of repeated transfusions, e.g. in s-thalassemia major, or due to excessive dietary iron uptake in anemias and hereditary hemochromatosis. Excess iron is deposited in the form of hemosiderins (insoluble “iron cores” of ferritin) mainly in the liver, spleen, many endocrine organs and in the myocardium. The exact mechanism of iron damage to these tissues is unknown, but it is established that organ failure correlates with iron burden in these tissues. Except for infectious diseases, cardiac complications are the major cause of death in s-thalassemia major patients.

4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoesäure: ein neuartiger, effizienter und selektiver Eisen(III)-Komplexbildner

Einen auserordentlich stabilen 1:2-Komplex [FeL2]3− bildet der Ligand H3L (siehe Formel) mit FeIII. Seine Affinitat fur andere Biometalle ist dagegen vergleichsweise klein. Diese Eigenschaften machen ihn zu einem vielversprechenden Kandidaten fur medizinische Anwendungen (z. B. zur Therapie der Eisenuberladung).

Screening and Application of Microbial Esterases for the Enantioselective Synthesis of Chiral Glycerol Derivatives

A number of enzymes with reasonable to excellent selectivities for the conversion of prochiral 2-benzylglyceroldiacetate 1c into optically active monoacetate 2c could be identified in a screening of microbial esterases and lipases. For the synthesis of the S-enantiomer of 2c by hydrolysis, two enzymes (from Aspergillus fumigatus and from Mucor javanicus) were identified which give the product with an e.e.-value of 75%. The R-enantiomer can be obtained with a purified lipase/esterase from Pseudomonas fluorescens in 96% e.e. The optical purity of the product was determined without derivatisation by chromatography on a chiral HPLC-column.

d-Ribulokinase from Klebsiella pneumoniae for continuous production of d-(−)-ribulose-5-phosphate

SummaryThe production of d-ribulose-5-phosphate in an enzyme membrane reactor was examined. Phosphoryl transfer from ATP to d-ribulose was catalysed by d-ribulokinase isolated from Klebsiella pneumoniae. For production of d-ribulose-5-phosphate the phosphoryl donor ATP was used either in stoichiometric or in catalytic amounts. Using catalytic amounts of ATP requires a second enzyme, e.g. pyruvate kinase, to regenerate ATP. The kinetic parameters for d-ribulokinase and pyruvate kinase were determined to calculate the performance of an enzyme membrane reactor for continuous production of d-ribulose-5-phosphate. Both processes operated for more than 200 h. Regardless of whether ATP was used in catalytic or stoichiometric amounts, about the same production parameters were determined. In continuous production space/time yields of 117 g (with ATP regeneration) and 103 g (without ATP regeneration) of d-ribulose-5-phosphate 1−1 per day were reached.