PPAR gamma modulators
Design of small drug-like molecules with a favorable Blood Brain Barrier profile.
Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors (NRs) that regulate lipid and carbohydrate homeostasis, currently targeted for treatment of peripheral diseases such as diabetes. The gamma subtype of this receptor (PPAR-gamma) is highly expressed in the central nervous system (CNS), both in neuronal and glial cells, where it exerts anti-inflammatory actions. In vivo studies have suggested that PPAR-gamma agonists prevent neuron degeneration and suppress glial activation in the SNc in acute and chronic MPTP mouse models of PD. Therefore, these compounds are among the most promising new disease-modifying therapies. However, limits to further investigations are the low selectivity and low permeability to the blood-brain barrier (BBB) of currently available compounds.
SMAC mimetics - malignant pleural mesothelioma (MPM)
Design of small molecule peptidomimetic antagonists of IAPs, pharmacophorically equivalent to the key IAP binding motif present in SMAC (second mitochondria-derived activator of caspases).
MPM is an aggressive, invariably fatal, treatment-resistant tumour, which is increasing in frequency throughout the world. MPM has been unambiguously associated with exposure to asbestos for half a century with the onset of disease occurring typically 20-50 years post exposure to the causal agent. Mean latency is >40 years. MPM is inoperable in ~90% of cases and metastases occurs in up to 75% of MPM patients. Contrary to belief that curbs in asbestos use have negated the condition, global incidence of MPM continues to increase. Up to 10,000 asbestos-related mesotheliomas occur annually across the population of Western Europe, North America, Japan and Australia. Western Europe will see a doubling of mesothelioma instances by 2020. Thereafter the future occurrence of mesothelioma can be predicted from the pattern of asbestos use around the world. Post 2020 the peak of the epidemic will shift towards countries and regions that have only recently banned or still produce/use large quantities of asbestos—e.g., Japan, Korea, Russia, China, Canada, South America, Africa, India and Thailand. Statistically, every 170 tons of produced and consumed asbestos will cause at least one death from mesothelioma. Currently over 70% of the world production of asbestos - ca 2m tons per annum - is used in Eastern Europe and Asia. There also are no data available to support the optimistic hypothesis that MPM cases in those nations who have acted to limit asbestos use and exposure would sharply decline in the first half of the 21st Century. Rather, in the US, a gradual decline to background levels (2 cases / million/ year) is predicted by 2055. In 10-15% of cases no association with asbestos is seen. Significantly other non banned, non-asbestos-classed fibres, including carbon nanotubes as well as genetic, viral and environmental causal elements have also now been linked to MPM. These epidemiological data indicate that mesothelioma will remain a significant cause of morbidity and mortality globally throughout the first half of this century and beyond.
Glucocorticoids antagonists - Antidepressant
Lead optimization of GR small drug-like antagonists with enhanced BBB permeability
The Glucocorticoid Receptor (GR) is a steroid hormone-activated transcription factor known to regulate numerous physiological functions of the endocrine and immune systems including adaption to physiological or psychological stress, through the action of cortisol - the major endogenous glucocorticoid hormone in humans. In this respect, there has been considerable interest in discovering selective small molecule modulators of GR.