Abstract
In this study, we report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of the adenosine triphosphate (ATP) binding site driven by structure-based drug design. For an upscale compatible multigram synthesis of the functionalized pyrrolidine scaffolds, we used a chiral pool synthetic route starting from methionine. Biological evaluation of key compounds in kinase and cellular assays revealed significant effects of the scaffolds towards activity and selectivity, however, the absolute configuration of the chiral moieties only exhibited a limited effect on inhibitory activity. X-ray crystallographic analysis of ligand-CK1δ complexes confirmed the expected binding mode of the 3,4-diaryl-isoxazole inhibitors. Surprisingly, the original compounds underwent spontaneous Pictet-Spengler cyclization with traces of formaldehyde during the co-crystallization process to form highly potent new ligands. Our data suggests chiral “ribose-like” pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds.
Highlights
To date, many drug discovery programs have been based on commercially or readily available building blocks and reagents to enable rapid synthesis of large compound libraries destined for various screening campaigns [1]
We have modified diaryl‐isoxazole 8 with functionalized enantiopure pyrrolidine scaffolds (Scheme 1) to promote selective binding interactions in the more hydrophilic areas of the adenosine triphosphate (ATP) binding pocket. These kinds of pyrrolidines scaffolds have been frequently used in various medicinal chemistry projects, including the development of glycosidase inhibitors, azanucleosides and antiviral agents [34,35,36,37,38]
We have modified diaryl-isoxazole 8 with functionalized enantiopure pyrrolidine scaffolds (Scheme 1) to promote selective binding interactions in the more hydrophilic areas of the ATP binding pocket
Summary
Many drug discovery programs have been based on commercially or readily available building blocks and reagents to enable rapid synthesis of large compound libraries destined for various screening campaigns [1]. This approach often resulted in collections of large, “flat”, achiral and low-diverse molecules [2,3]. In this context, the “quality” of compounds and building blocks in terms of complexity, carbon bond saturation, chirality or natural product-likeness has been intensively discussed in the medicinal chemistry community [4].
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