Entwicklung von neuroprotektiven Wirkstoffen basierend auf Amiden des 4-Phenoxyanilins und verwandten Verbindungen

Neuronal cell death is the underlying pathomechanism of several neurodegenerative diseases. Different stimuli trigger the programmed cell death via mitochondrial demise caused by members of the Bcl-2 family. One of the key players is the proapoptotic protein Bid (BH3 interacting domain death agonist). In 2004, the group of PELLECCHIA published the structure of a first inhibitor that resulted from a NMR-based fragment approach to target the interaction of Bid with other proteins. The substance BI-6C9 displayed strong protective effects against tBid-induced cell death in several in vitro experiments. Unfortunately, the compound showed no activity in vivo. In a first approach, three moieties of the model-substance were replaced by alternatives derived from a scaffold hopping strategy. This resulted in inactive compounds. In the present thesis the inactive structure was synthetically modified and lead back to the parent compound BI-6C9. It could be shown, that all replaced moieties are responsible for the high activity of the compound. Introduction of a nitro-group as substituent on the p-position of the aromatic sulphonamide shows the possibility of creating compounds with enhanced neuroprotective properties. Moreover, several series of smaller compounds were derived from the fragment 4- phenoxyaniline. A compound with promising neuroprotective features was the amide of 4-phenoxyaniline and piperidine-4-carboxylic acid. For further synthetic modifications, the molecule was subdivided into three moieties that were subsequently exchanged or modified, in order to obtain information about structure-activity-relationships. Variations of moiety C (piperidine-nitrogen) gave a heterogeneous picture. The most interesting derivatization of the piperidine nitrogen was an acylation with β-alanine. The compound displayed significant protective effects at a concentration of 1 µM in a model system of neuronal cell death, the toxicity of the compound was moderate. Since the piperidine-nitrogen seems to be associated with the toxic effect of the compounds, several replacements for moiety B were introduced. In a previous thesis, a derivative of 4-phenoxyaniline and succinic acid methyl ester showed considerable neuroprotective activity. In order to establish SAR, the length of the linker between the two carbonyl groups was modified and also moiety A (biaryl-motif). The influence of this moiety on the compounds activity was less important than in the other series. The linker length of succinic acid appeared to be suited. Also several antioxidant moieties were introduced as replacement for moiety B, with the aim to produce compounds with dual effects on the prohibition of cell death induced by oxidative stress. A derivative of 3,5-Dimethoxy-4-hydroxycinnamic acid displayed full protection of the neurons against glutamate-induced cell death in concentrations as low as 5 µM. An interesting replacement for the piperidine-4-carboxylic acid is tranexamic acid. In combination with 4-(4-nitrophenylsulfanyl)aniline as moiety A, a very potent com-pound could be synthesized. However, the high toxicity of the substance is not favourable for further development. In the last series, systematic modifications of moiety A were conducted. The linking group between the two aromatic rings was exchanged. An amino group and a thioether emerged as the most suitable replacement for the oxygen-atom of the parent compound. During the modifications of moieties B and C, substituents at the 4´ position of the biaryl-motif of moiety A have been introduced to get a first impression about the influence of this structural feature. In the last step, several structurally diverse groups were introduced on this position. Four substituents emerged as interesting combination partners for the other elements. A trifluormethyl group, a cyano group, a nitro group and an amino group lead to compounds with increased neuroprotective properties. In future experiments, combinations of the above mentioned structural elements will have to be synthesized. Derivatives of 4 (4 nitrophenylsulfanyl)aniline include a nitro group at the 4´-position of the biaryl-motif in combination with a thioether and displayed good neuroprotective activity. This example could be a prospect of additive or even synergistic effects.