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Following the high-profile ENHANCE trial, in which addition of the cardiovascular drug ezetimibe to statin therapy did not result in additional improvement in an imaging-based measure of atherosclerosis, what are the implications for such studies in the future?
High-throughput profiling of compound libraries against large panels of kinases is becoming technically feasible. In contrast to the traditional linear, target-centric approach to discovery, this approach may provide a choice of targets to pursue that is guided by the quality of lead compounds available, rather than by target biology alone, and could thereby significantly improve the productivity of kinase inhibitor discovery.
The renin–angiotensin system, which is a key regulator of blood pressure, has been successfully targeted by several classes of drugs for the treatment of cardiovascular disease. However, renin — the protease at the top of the cascade — although highly attractive as a target, has also proved to be challenging. Here, we describe how these challenges were tackled in the discovery and development of aliskiren, the first renin inhibitor to be approved for clinical use.
TWEAK, a member of the tumour necrosis factor superfamily, is a multifunctional cytokine that acts on cells by binding to a small cell-surface receptor named Fn14. Here, Winkles summarizes the biology of the TWEAK–Fn14 axis and describes the recent evidence supporting the notion that this axis could be a therapeutic target for the treatment of cancer, chronic autoimmune diseases and acute ischaemic stroke.
There is mounting evidence of the involvement of the glutamatergic system in mood-disorder pathophysiology as well as of the efficacy of glutamatergic agents in mood disorders. In this Review, the authors examine the contribution of abnormalities in the glutamatergic system to the impairments in neural plasticity that are observed in patients with mood disorders, and how this knowledge can be applied to the development of antidepressants with more rapid and sustained effects.
In this Review, the author discusses how prolonging the lifespan of endocannabinoids or toning down their action may be beneficial in a range of conditions such as pain, affective and neurodegenerative disorders, gastrointestinal inflammation, and obesity and metabolic dysfunctions.
