Innovative targets for circadian drug discovery: REV-ERBalpha and RORalpha

Humans are rhythmic beings, with daily sleep/wake cycles affecting almost every aspect of physiology and behaviour. Our master circadian clock is known to reside in the suprachiasmatic nuclei (SCN) of the hypothalamus. Via multiple pathways, output from the SCN synchronizes peripheral oscillators throughout the body. The discovery of the molecular components of the core clock has provided new insight into the link between circadian biology and chronic diseases, but has not been exploited for drug discovery. With this work we will prepare chemical probes for the clock proteins REV-ERBalpha and RORalpha, characterise their activity in models of inflammation, and deliver lead optimised molecules for clinical development.

The synthetic chemistry described is part of a wider programme involving a fully integrated drug discovery programme with the initial aim of generating high quality chemical probes to establish the two orphan nuclear receptors REV-ERBalpha and RORalpha as innovative targets for respiratory disease. The targets will be validated in models of inflammation including asthma and chronic obstructive pulmonary disease (COPD). COPD was the 6th highest cause of death worldwide in 1990 and is estimated to rise to 3rd highest by 2020. In the USA it is currently the 4th highest cause of death, with an estimated 16 million sufferers while another 16 million are undiagnosed (American Lung Association). The annual economic burden of COPD in the USA is estimated at $42.6 billion in health care costs and loss of productivity. Asthma effects 7% of the world's population with an estimated 300 million sufferers and is reported to be responsible for 4000 deaths in the USA per year. The need for innovative medicines acting via novel mechanisms of action to tackle these debilitating disease states is clear and the probes developed in the early stages of this project will be progressed towards clinical candidates. In addition, full dissection of the roles of these nuclear receptors in circadian biology could provide targets for other chronic disease states of interest including rheumatoid arthritis, metabolic disease, neurological disease and cancer and the collaborative network to examine these possibilities has been established.