In order to demonstrate the practical application of the CADDIS® process, Matrix Pharma undertook an in-house research project with the objective of identifying and developing a direct thrombin inhibitor.
The lead compound that has been identified is very promising. It is currently completing preclinical testing and has demonstrated very favourable results in terms of its specificity, toxicity, absorption, and metabolism.
Thrombin was chosen as the target because it is so well known in the research community, and because the financial implications for the pharmaceutical industry of an orally available thrombin inhibitor are considerable. Any work done by Matrix in this field could easily be compared with the efficacy of other processes such as X-ray structure analysis and 3D modelling, and the thrombin inhibitor market is projected to be worth close to USD 15 billion by 2011 (source: DataMonitor).
The general requirements for a direct thrombin inhibitor have been well-characterized in the literature (Hauptmann, J., Stürzebecher, J.; Thrombosis Research 93 (1999) 203-241). Matrix Pharma initiated the CADDIS® process assessing candidate drugs based on the following criteria:
Main Criteria:
• Inhibition of Thrombin, high - Efficacy
• Inhibition of Trypsin, low - Selectivity
• HeLa cells - Cytotoxicity
• Hemolysis
Further Criteria:
• Serum Protein Binding (SPB)
• Metabolic Stability
• Solubility
Additional measured values (not included in the optimization cyles):
• Ames Test - Mutagenic, Carcinogenic Potential Permeability
After 8 cycles, CADDIS® identified five potent, highly selective, relatively non-toxic, and well absorbed antithrombotic drugs that were licensed out to BioLineRX (www.biolinerx.com) for their continued preclinical and clinical development.
Discovery of these compounds was achieved by screening only ~1,000 molecules over a one year period, as compared to more than 10,000 molecules over 2 to 4 years for conventional Pharma methods, and at 10% of their cost.
Click here to request a copy of the article entitled "Thrombin inhibitors identified by computer-assisted multiparameter design" that appeared in the Proceedings of the National Academy of Sciences (PNAS) (June 14, 2005; vol. 102, no. 24, p. 8597-8602).
Click here to request a copy of Matrix Pharma's "Thrombin Inhibitor - White Paper" that provides additional details regarding this discovery project.
