Ludwig Zorn

Identification of novel GLUT inhibitors

The compound class of 1H-pyrazolo[3,4-d]pyrimidines was identified using HTS as very potent inhibitors of facilitated glucose transporter 1 (GLUT1). Extensive structure-activity relationship studies (SAR) of each ring system of the molecular framework was established revealing essential structural motives (i.e., ortho-methoxy substituted benzene, piperazine and pyrimidine). The selectivity against GLUT2 was excellent and initial in vitro and in vivo pharmacokinetic (PK) studies are encouraging.

Biocatalysis at Work: Applications in the Development of Sagopilone

For the antitumour agent sagopilone, an epothilone analogue, a large‐scale synthesis was developed to synthesise the active pharmaceutical ingredient for clinical trials, exploring enzymatic and microbial methods to produce chiral building blocks on a multi‐kilogram scale. The three building blocks were identified as key intermediates in the synthesis and needed to be produced with high optical purity in yields higher than those previously published. The improved syntheses of two of these building blocks are detailed herein. For building blocku2005A, the chemical research synthesis was abandoned, and a novel chemical route was developed leading to building blocku2005A via an enzymatic hydrolysis process. For building blocksu2005C, replacement of a chemical catalytic procedure by a microbial process meant that the development of a new starting material could be avoided, thereby accelerating the development process. For the clinical development process, a human metabolite of sagopilone was required as a reference. To accelerate the synthesis of the metabolite, no chemical synthesis was investigated; rather, we relied solely on oxidoreductases. The human metabolite of sagopilone was synthesised on a multi‐gram scale in a single‐step process using genetically engineered E.u2005coli expressing human cytochrome P450 enzyme 2C19. The integration of enzymatic and microbial processes provided tools that enable the synthesis of highly functionalised intermediates and metabolites.