Background to the AMcore™ Bicyclic Core Molecular Scaffold
 Peptidases in general
Peptidases are enzymes (catalysts) that hydrolyse peptide bonds and thereby cleave proteins. They play a crucial role in the regulation of a wide range of physiological processes. Aberrant peptidase activity is associated with the onset and maintenance of many disease states. In addition, peptidases have been shown to be important in the establishment and propagation of parasitic, bacterial and viral infections, thus representing a potentially novel route to the therapeutic management of many pathogenic diseases.
There are currently six main classes of peptidase:
- Aspartic acid peptidases
- Cysteine peptidases
- Metallopeptidases
- Serine peptidases
- Threonine peptidases
- Glutamic acid peptidases
General information of peptidases: link here
Search MEROPS peptidase database: link here
Peptidase inhibitors in the clinic
The majority of successful peptidase-targeted drugs principally affect three of the main classes of peptidase:
- Saquinavir® & Ritonavir® are marketed inhibitors of HIV aspartyl peptidases;
- Argatroban monohydrate inhibits thrombin in the treatment of peripheral arterial occlusive disease;
- Captopril® & Enalapril®, ACE (angiotensin-converting enzyme) inhibitors, are used to treat hypertension related disorders, and
- Marimastat®, an inhibitor of MMP-1 (matrix metalloprotease-1), used to treat inflammation and cancer.
For a general review on protease inhibitors in the clinic: link here
Currently, there is no marketed product that targets the fourth main class of peptidase, cysteinyl peptidases. Within the cysteinyl classification, peptidases are grouped into clans based upon properties such as activity and structure. Amura is currently focusing on the papain-type cysteinyl peptidases (clan CAC1).
Peptidases as therapeutic targets
To date over five hundred mammalian peptidases have been identified of which more than one hundered and fifteen are cysteinyl peptidases including fourteen CAC1 peptidases (the cathepsins). In humans, eleven cathepsins are known. Many of these represent bona fide therapeutic targets, making the CAC1 field an extremely attractive area of research and development that already spans numerous disease indications.
Prior to the year 2000, cathepsin-inhibiting compounds in development relied on a monocyclic ketone or a nitrile group 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 proved liable to turnover through the action of nitrilases. In principle, all thiol peptidases including cysteinyl peptidases have potential nitrilase activity suggesting that nitrile compounds will not be amenable for these clinical targets.
Amura has designed and tested a fundamentally new class of compound characterised by a bicyclic core structure, AMcore™. The benefits of these new compounds include: chiral stability; absence of a nitrile group; aqueous solubility and a lack of intrinsic toxicity consistent with their development as systemic drugs. A “butterfly wing” conformation across the bicycle docks favourably with the major binding groove of many classes of peptidases, and in particular cathepsins (CAC1 peptidases).
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