ORGANOCATALYSIS · Versatile and environmentally friendly new reaction methodology for synthetic organic chemistry with application to medicinal chemistry

Final Activity Report Summary - ORGANOCATALYSIS (Versatile and Environmentally Friendly New Reaction Methodology for Synthetic Organic Chemistry with Application to Medicinal Chemistry)

For the outgoing phase of the research project, the research objective was to develop a new enantioselective organocatalytic reductive amination for the preparation of chiral amines. The project was elaborated from initial concept through successful completion via design of a new chiral Bronsted acid catalyst to facilitate the process on a range of substrates. The results were communicated in a leading international journal and the article became the second most cited paper of 2006 in that journal. The new catalyst was recognised by commercial suppliers and would be available for purchase shortly after the project completion. For the incoming phase research project objectives were, as part of a project team within the respiratory and inflammation therapeutic area, to develop an aggrecanase inhibitor as a treatment for osteoarthritis. In general, the inhibitors of aggrecanase that were developed contained a zinc-binding group such as a reverse hydroxamate group. These zinc-binding motifs proved to be essential to gain activity. In addition to the zinc-binding group there were two other key portions of the molecule, referred to as P1 and P1' groups. They were named directly in accordance with the enzyme pocket into which they bound, known as the S1 and S1' pockets respectively. Modification of these groups permitted the ability to tune reactivity, selectivity and physical properties of the molecules. A range of molecules of this generic type were systematically designed, synthesised and tested as inhibitors against a range of a-disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and Matrix metalloproteinases (MMP) enzymes. Molecules with a diverse range of both P1 and P1' groups were synthesised using similar chemistry. Overall, this facilitated the development of molecules that efficiently targeted the desired enzyme and simultaneously possessed useful enzyme selectivity, physical properties and pharmacokinetics. The crystal structure of a related enzyme was known and provided vital information and approximations as an aid to rational compound design. In summary, breakthroughs towards progressing key target molecules to the next stage of development were achieved as part of an established multidisciplinary project.

Data: CORDIS, © European Union