AbstractDiseases of the central nervous system represent an increasing area of unmet medical need. Despite high levels of investment from the pharmaceutical industry few disease modifying drugs have been discovered with the most common cause of late stage clinical failure being a lack of efficacy. In order to enable greater understanding of disease mechanisms and the ability to validate specific biological targets for disease intervention, there is a need for medicinal chemists to identify high quality chemical compounds which can reliably probe new therapeutic concepts. Herein, I report three approaches towards this goal.
In the first case, a structure based approach allowed the de novo design of a novel class of D-amino acid oxidase (DAAO) inhibitors. This work gave rise to three novel series of DAAO inhibitors, all of which were capable of addressing some or all of the issues that had limited previous attempts to inhibit this high profile CNS target. Furthermore, subsequent optimization by colleagues of chemical leads I discovered and detailed within this thesis, led to the identification of clinical candidate TAK-831.
In addition, novel inhibitors for Cholesterol-24-hydroxylase (CH24H) are shown, developed via a property guided approach. The advantages of balancing physicochemical properties throughout lead molecules are demonstrated, giving rise to compounds with in vivo activity in rodent models of spatial learning and memory deficit for this novel drug target. Finally, a strategy for the efficient synthesis of diverse and highly lead-like screening libraries is presented specifically with the objective of providing improved molecular starting points for CNS drug discovery.
|Date of Award||2019|
|Supervisor||Alessio Ciulli (Supervisor) & Kevin Read (Supervisor)|