Discovery & Development of Xanamem

Discovery & Development of Xanamem

Pioneering research over a number of years at the Centre for Cardiovascular revealed the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) as a therapeutic target for the potential treatment of cardiometabolic disease and memory impairments. This research catalysed considerable efforts by the pharmaceutical industry to develop new anti-diabetic therapies culminating in the discovery of agents such as AMG-221 and BI-135585.

Supported by Wellcome Trust Strategic Translation and Seeding Drug Discovery funding we (Prof Brian Walker, Prof Jonathan Seckl and Dr Scott Webster) embarked on an in-house translational research programme to discover and develop novel 11ß-HSD1 inhibitors for the treatment of memory loss in Alzheimer’s disease. We worked closely with industry partners to deliver key aspects of the programme, including medicinal chemistry.

Initial medicinal chemistry focussed on a series of amide analogues that demonstrated moderate in vitro potency in cellular assays (Figure 1).

Figure 1. Xray structure of an amide analogue bound to murine 11ß-HSD1.

Further medicinal chemistry was carried out, which diversified the choice of molecules available for optimisation (Figure 2).

Figure 2. Hit to lead optimisation of amide analogues.

The discovery of UE2316 allowed us to establish efficacy in models of Alzheimer’s disease. This work was published in Endocrinology and showed that treatment with UE2316 improved memory and reduced the amount of ß-amyloid plaques in key regions of the brain (Figure 3).

Figure 3. Improvement in memorry and reduction in ß-amyloid plaque number in an Alzheimer's disease model.

Additional medicinal chemistry was carried out to increase potency and to improve the pharmacokinetic characteristics of UE2316 so that it could be administered in tablet or capsule form to humans once or twice daily. This resulted in the discovery of a new, potent molecule (UE2343) which possessed properties.suitable for administration to humans (Figure 4).

Figure 4. Optimisation of UE2343.

UE2343 entered Phase 1 clinical development in healthy human subjects where it demonstrated excellent pharmacokinetic and pharmacodynamic properties.UE2343 was subsequently licensed to Actinogen Medical, who renamed it XanamemTM. Xanamem is currently progressing towards Phase 2 clinical trials in patients with Alzheimer’s disease.