Novel strategies to access chiral heterocycles as potential lead compounds in drug discovery

The development of new medicines (drug discovery) is essential to improve the health of the world's population. Tackling current medical needs requires drugs that will work in new ways. Therefore, more complex biological interactions are being investigated as targets. However, finding good starting points for drug development that will act against these complex biological targets presents a formidable challenge.

Historically, starting points for drug development, known as lead compounds, came from natural small molecules that bind to the target. However, these are often not available, particularly in complex binding interactions. The screening of compound collections in the pharmaceutical industry has also been largely unsuccessful in finding lead compounds for more complex targets. This is because industrial compound collections are often clustered around relatively few structural types and are frequently reliant on flat (non-chiral) structures. Alternative methods are required for the generation of more diverse and 3-dimensional (chiral) molecules that may function as drug-leads. Indeed the pharmaceutical industry is currently interested in focussing on fewer, higher quality lead compounds.

This research will develop new chemical methods to enable the synthesis of diverse molecular frameworks with the potential to be lead compounds in drug discovery. These frameworks will be centred around chiral (3-D) heterocycles. Heterocycles are carbon based ring structures that contain at least one heteroatom in the ring (i.e. an oxygen, nitrogen or sulphur atom) and are frequently essential components of drug compounds. Chiral heterocycles in particular offer ideal properties for quality lead compounds, being small with desirable physical properties as well as having a defined 3- dimensional shape, which is crucial to structural and binding interactions with biological systems.

The synthesis of these complex heterocyclic molecules from simple, readily available starting materials is of fundamental interest and a major synthetic challenge. The key synthetic innovation of this proposal is the invention, development and application of new chemical reagents to achieve this goal. These reagents contain multiple functionality, important in performing multiple roles in the synthesis. Synthetic methods will be developed for three classes of chiral heterocycles with control of the 3-D shape. Furthermore these synthetic methods will allow a wide variety of chemical groups to be introduced directly onto the heterocyclic core of the molecule. This will enable rapid access to diverse molecular frameworks not currently well represented in industrial compound collections.

Compounds generated by these new methods are of interest as potential lead compounds against a wide variety of biological targets. To demonstrate this, a series of analogues will be prepared of a compound known to disrupt the interaction between two proteins that is implicated in various types of cancer. Future collaborative research is envisaged to evaluate the now accessible compounds against biological targets. Furthermore, the new chemical reagents and the synthetic methods developed in this research will be widely applicable in fields of chemical synthesis and medicinal chemistry.

The pharmaceutical and agrochemical industries in the UK are expected to be the most significant beneficiaries. The pharmaceutical industry is in a period of upheaval due to failure of drugs to get to market and loss of patent protection on blockbuster drugs. This, combined with the failure of screening collections against emerging targets makes new approaches to the development of quality screening collections a pressing endeavour. Furthermore there is increasing demand for novel chemical libraries to identify biologically active targets to match the rapid advances in genomic and proteomic approaches.

The following outcomes of the research may have impact for these beneficiaries:
i) Synthetic strategy:
The strategies developed by this research will provide new approaches to the preparation of compound types desirable for their biological activity. It will provide flexibility to introduce a diverse array of substituents directly onto the heterocyclic core to provide both framework diversity and structural complexity hence enabling rapid access to areas of unknown bioactive chemical space, not accessed by traditional libraries.
ii) Improved methods to access desirable structural types:
The beneficiaries may take advantage of the specific methodology developed by this research to access structural types that are currently desirable in medicinal chemistry but that do not have efficient methods for their preparation.
iii) The compounds themselves:
Testing of the diverse arrays of compounds generated by this research may lead to interesting biological activity or lead-compounds for further development. This may be achieved by direct collaboration with industry or through academic collaboration leading to future industry collaboration. For example Lilly provide phenotypic screens offered without charge, which focus on compounds of novel structural diversity, for which these structures would be relevant candidates.
iv) Reagents as generally applicable in synthetic chemistry:
Reagents developed in this research and the increased understanding of their reactivity may find broader use in synthetic chemistry by industry scientists in alternative synthetic programmes, in the discovery or development stages of a drug discovery programme.

The increased regulatory pressure and pressure on pricing by healthcare systems means that increased efficiency is vital in terms of time, resources and waste. The chemistry developed here will allow ease of initial synthesis and subsequent ease of structural optimisation, providing a strategic advantage in medicinal chemistry research where extensive iterative analogue synthesis is required. This will reduce the time required for discovery, the number of synthetic operations and the cost leading to positive economic and environmental impacts. Increased efficiency in drug development would provide lower cost healthcare to government healthcare systems and the patients. Ultimately, through any of these avenues this research may aid in the successful development and commercialisation of a drug compound, which would be beneficial to the UK economy. New drug compounds would be beneficial to the health and well being of the UK population.

The successful development of novel and efficient synthetic routes to these ring structures and methods of functionalisation may lead to patentable results or procedures and further development through licensing. The research contributions of the PhD students will make them well placed for professional contribution to the UK pharmaceutical or agrochemical industries.