A single enzyme in the liver, fat, and brain acts as a biological volume knob for the stress hormone cortisol, and a team in Edinburgh has developed a series of drug candidates to turn that knob down. This matters because when the enzyme—11-beta-HSD1—amplifies cortisol too much, it drives the cluster of conditions known as Metabolic Syndrome: obesity, insulin resistance, high blood pressure, and cognitive decline in ageing. The researchers have already shown in both animals and humans that blocking this enzyme improves those symptoms and sharpens memory in older people. If the project succeeds, a single pill could treat multiple age-related problems at once—reducing the need for separate drugs for diabetes, obesity, and cognitive decline. The team has three chemically distinct series of inhibitor compounds with proven potency and safety in animals. They now plan to run full preclinical toxicity and efficacy studies, then select one candidate for first-in-human Phase I trials. The work is a direct translation of fundamental discoveries about cortisol regulation, funded by the Wellcome Trust since 1990, into a tangible clinical candidate.
View original technical description
With Wellcome Trust support, including Programme Grant (1990-2012) and sequential (1999-2002; 2003-2005) Development Fund awards, we identified 11-beta-HSD1 as a crucial amplifier of glucocorticoid action in liver, adipose tissue and CNS; showed its pathophysiological significance in obesity; and provided preclinical and clinical proof of concept' that 11-beta-HSD1 inhibition improves Metabolic Syndrome and cognitive function in ageing. With our current Strategic Translation Award (2006-2008) we combined our internationally-leading academic strengths in biology and structural biology in Edinburgh with out-sourced medicinal chemistry to develop three chemically distinct series of novel 11-beta-HSD1 inhibitor hits. We have identified and patented a series of pre-clinical candidate compounds with favourable potency, selectivity, SAR (including co-crystallisation), physicochemical properties, metabolic stability and in vivo pharmacodynamics and pharmacokinetics. We now propose fully to optimize advanced lead candidates with comprehensive preclinical pharmacokinetic, pharmacodynamic, toxicity and efficacy studies, and select and advance one clinical candidate into Phase I. Our established project team provides biology, medicinal chemistry and lead optimisation expertise alongside globally-leading experimental medicine capabilities and will be augmented with professional consultants in formulation & manufacturing (Advocates) and early clinical development (Gregory Fryer Associates; Alan Boyd). This strategy aims to maximize the benefits to human health arising from Wellcome Trust-funded research.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know