Case Study 2 - 11β-HSD-1

steroid to non-steroid

The search template

An interesting validation of Cresset's technology came from a screen looking for antagonists of the steroid receptor, 11β-HSD-1. No crystal structure of the target was available at the time. A field template was derived from the known SAR around the natural steroid ligand (cortisone). This was used to search our database of commercially-available molecules.

A total of 408 compounds were purchased as a result of the search and screened. Of these, 23 were found to be active (5.6%), with the actives approximately clustered into four structural series. The best actives were sub-micromolar (470 and 170nM) and bore no resemblance to the steroid ligand. All four series were small lead-like compounds with straightforward chemistry and no obvious ADMET liabilities. One of the series (the tetrazoles) has now been patented by our client (WO2007029021) and close analogues of two of the other hit series have been patented by other companies (AstraZeneca and Incyte).


The tetrazole hit patented by Cresset's client	The hit compound similar to the AstraZeneca patent	The hit compound similar to the Incyte patent