Suberone-based type I½ p38α MAPK-inhibitors with improved properties to treat colorectal cancer

Abstract

The aim of this thesis was the design and synthesis of novel p38α MAPK inhibitors to gain a better understanding of the SAR and the interaction of the type I ½ residues with the R-spine. Another aim was the optimization of the ADME-properties, particularly solubility and metabolism. Within the scope of this thesis, 74 novel p38α MAPK inhibitors were synthesized. Many inhibitors demonstrate excellent inhibitory activity against the isolated kinase with IC50-values in the single-digit nanomolar or even picomolar range. Moreover, new concepts to optimize the metabolic stability were established. Thus, the major drawback of the amide-based inhibitors is the metabolic cleavage of the type 1 ½ amide residues resulting in a type I inhibitor. The replacement of the amide bond through a metabolically more stable functional group enabled the prevention of the type I ½ residue cleavage. As new functional groups inter alia ketones, imides and oxadiazoles were used. Concepts to improve the solubility were also utilized. Therefore, heteroatoms to reduce the lipophilicity were introduced and the number of C-sp3 atoms were increased to enhance the complexity of the compounds. The success of the solubility concept still needs to be proven by test data. Additionally, the synthesis of the dibenzosuberone scaffold was optimized. By utilizing an alkyl-Suzuki coupling reaction a two-step synthetic route with an improved overall yield of 85% instead of 66% was developed. Furthermore, a new class of p38α MAPK inhibitors with an additional nitrogen attached to the B-ring of the tricyclic dibenzosuberone scaffold were designed. The aim thereof was the optimization of the kinase interaction and to improve the solubility. The azadibenzosuberones show high activity against the isolated p38α MAP kinase with IC50-values up to 40 picomolar. Unfortunately, the extraordinarily high activity could not be confirmed in the whole blood assay