A New Approach
Amura has designed and tested a fundamentally new class of cathepsin inhibitor characterised by a “butterfly wing” bicyclic core scaffold, termed AMcore™. Our AMcore™ derived lead candidates exhibit attractive properties that include: chiral stability; absence of a nitrile group; good aqueous solubility and a lack of intrinsic toxicity consistent with their development as systemic drugs. Lead candidates exhibit fully reversible “fast on / slow off” kinetics providing an ideal profile for drug development.
A vast array of modifications are possible based on the AMcore™ structure; enabling the design of drug candidates against a broad range of different CAC1 peptidases. Deployment of different chemical moieties, drawing on Amura’s proprietary structure activity relationship (SAR) database, allows selectivity and high-affinity binding of compounds against distinct targets, whilst retaining a lack of activity against other closely related peptidases.
Competitor cathepsin inhibitors in development rely upon a monocyclic ketone or a nitrile warhead to provide the required inhibition of the target peptidase. However, monocyclic ketones have been shown to be chirally unstable through enolisation whilst nitrile compounds have proven liable to turnover through the action of nitrilases. In principle, all thiol peptidases including cysteinyl peptidases have potential nitrilase activity suggesting that the clinical evaluation of nitrile compounds, particularly for chronic indications, may be problematic. Indeed, two peptidyl nitriles have recently been suspended in the clinic due to adverse skin reactions.
Our lead candidates are actively being exploited for diseases such as osteoporosis, bone metastasis, osteoarthritis and autoimmunity (e.g. rheumatoid arthritis, psoriasis) and chronic pain.
Download the AMcore™ factsheet here