Immunomodulatory drugs containing active ingredients such as thalidomide, lenalidomide and pomalidomide are mainly used in the treatment of multiple myeloma. They are also used in proteolysis targeting chimera (PROTAC) technology due to their affinity to the E3 ligase cereblon. PROTAC are hetero-bifunctional molecules consisting of three parts: a ligand that binds to the E3 ubiquitin ligase, a suitable linker and a ligand that binds to the target protein. The formation of the three-component complex leads to ubiquitination of the target protein, followed by degradation by the proteasome. By targeting more than 30 different proteins, PROTAC is used to treat a variety of cancers, immune disorders and neurodegenerative diseases. For finetuning of bioactivity, non-glutarimide analogs of the immunomodulatory drugs are highly sought after.
As part of the master's thesis, we prepared thalidomide and pomalidomide analogues in which one of the carbonyl groups of the glutarimide fragment is replaced by a bioisosteric trifluoroethyl group. The designed molecules have two chiral centers, therefore we have developed synthetic routes for the preparation of individual diastereomers. The structure of the compounds was confirmed by one- and two-dimensional NMR experiments and by mass spectrometry. Their physicochemical properties (solubility, partition coefficient) were evaluated experimentally and their pharmacokinetic properties were predicted using the SwissADME software. The compounds were prepared in amounts and purities enabling the evaluation of their bioactivity relative to the glutarimide agents.
We prepared nine final compounds, which, in general, demonstrated better physicochemical properties than glutarimide active ingredients. All compounds had better solubility in buffer pH 7.4 than glutarimides. In the series of pomalidomide analogs an intriguing trend was observed: the bioisosteric analogs are more lipophilic (logD7,4) and at the same time exhibit better solubility. All analogues had better predicted pharmacokinetic properties, among which we checked topological polar surface area (TPSA), blood-brain barrier penetration, whether the compounds are substrates for P-glycoprotein and CYP450 inhibition. Among all compounds, both diastereomers of compound 4 with the bioisosteric replacement at position six of the 2-aminoglutarimide and with tetrafluoro substitution on the phthalimide moiety, had the best properties. All compounds show potential for further development and will be evaluated as cereblon binders.
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