Design and Synthesis of 3-Dimensional Fragments to Explore Pharmaceutical Space

This thesis describes an approach to the design, analysis and synthesis of saturated nitrogen heterocyclic fragments to explore pharmaceutical space. Firstly, the development of a computational protocol for the shape analysis of fragments is described (Chapter 2). Principal moments of inertia (PMI) plots were used to generate a set of selection criteria to select compounds found in the 3-dimensional area of the PMI plot. The computational method was applied to different scaffolds, piperidine, pyrrolidine and azepane, to generate a 3-dimensional fragment library.

The computational analysis of a disubstituted piperidine fragment library provided a 20 compound sub-set library for synthesis. The progress of this synthesis is described (Chapter 3). Six final fragments have been prepared and synthesis towards ten of the other fragments is reported. The synthesis was planned with careful consideration of synthetic routes to minimise the number of different steps and routes employed.

Finally, the application of our computational protocol to a virtually enumerated lead-like library is presented (Chapter 4). The shape diversity and physicochemical properties of 190 different lead-like compounds from six different saturated nitrogen heterocyclic scaffolds is described. The analysis of these data to select compounds with suitable lead-like properties and interesting 3-dimensional shapes is summarised.