The PADMET platform - pharmacokinetic characterization of carbohydrate mimetics

More than two decades ago it was realized that drug discovery and development strategies focusing exclusively on affinity enhancement and potency are unsuccessful. Instead, simultaneous optimization of pharmacodynamic and pharmacokinetic properties has been proposed and implemented. As a result, new assays for pharmacokinetic characterization were required and existing assays were modified to fulfill high-throughput requirements. These assays, typically used at early stages of drug discovery and development, were modified and employed during this doctoral thesis to determine pharmacokinetic parameters of carbohydrate mimetics. The project was termed PADMET platform, with PADMET standing for physicochemical properties, absorption, distribution, metabolism, elimination, and toxicity. The aims of the platform were on the one hand the elucidation of the pharmacokinetic behavior of carbohydrate mimetics and on the other hand the development of such compounds with improved drug-likeness.
While building up the PADMET platform, the need for an inexpensive and uncomplicated pKa determination method became apparent. A methodology based on 1H-NMR spectroscopy was chosen for this purpose and scope and limitations of this approach were explored. An excellent correlation to reference data was achieved.
The components of the platform were used to characterize 93 carbohydrate mimetics regarding several pharmacokinetic parameters. The results were used in different projects of which two are discussed in detail in this thesis. First, one of the primary goals of the FimH antagonist project was the synthesis of orally available compounds with fast renal excretion. By the aid of various assays, molecules with a promising profile could be identified. Indeed, in vivo mouse studies confirmed the intended properties. The permeability values gathered during this project were correlated to calculated descriptors and to experimental lipophilicity values in order to identify the driving force of the permeation of carbohydrate mimetics. Calculated lipophilicity values as single descriptor proved to be superior to other descriptors and to combinations thereof.
Second, during the MAG project compounds with maintained local concentrations in the cerebrospinal fluid were envisioned. Permeation through artificial blood-brain barrier and stability in artificial cerebrospinal fluid were thus determined.