Biologically active compounds inhibiting calpain proteases with potential use for the treatment of acute conditions (e.g. ischemia) and degenerative diseases (particularly neurodegenerative diseases)

Background

Calpains are a family of proteases showing a deregulated activation under physiological stress. This finding has opened a door to a novel approach for the treatment of a number of diseases and conditions: stroke and traumatic brain injury, neuromuscular and neurodegenerative diseases (Alzheimer’s, Hungtinton’s and Parkinson’s diseases), muscular dystrophy, multiple sclerosis, atherosclerosis, etc. Thus, contrary to strategies focused on preventing or reducing initial events such as ligand-receptor binding or membrane depolarisation, calpain inhibition means acting on a post-receptor process, thus allowing more specific and efficient treatments.

Technology

We have synthesized isoquinoline and biphenyl derivatives showing high calpain inhibiting activity. In vitro experiments have resulted in IC50 at the nano- and picomolar level for several of these compounds. This represents 100-times higher inhibiting capacity as compared to other calpain inhibitors previously reported.The specificity of this inhibition was confirmed by testing similar compounds, which showed either no inhibiting or weak inhibiting activity against calpain.

Main features and advantages

• A novel approach acting on post-receptor processes
• Strong inhibiting activity
•  Specificity
• Promising toxicity results and capability to pass across the cellular membrane (as well as neuroprotective capacity) have been shown for  some of these derivatives in cell cultures
•  Four or less well known synthesis steps are required
• High yield synthesis with total selectivity (where relevant a single steroisomer and regioisomer is produced)
•  Reproducible synthesis at multigram scale has been achieved

Two PCT (“International”) patent applications filed. “National Phase” applications filed for one of these.

We are looking for companies to carry out optimisation of these compounds and/or develop pre-clinical studies.