Resolution Pharmaceutical Service Generates Metal-Containing Drug Libraries
Resolution Pharmaceuticals (Mississauga, ON) has launched a new contract research service that will produce large-scale libraries of novel metal-based pharmaceuticals, radiopharmaceuticals, and contrast agents for pharmaceutical and biotechnology company clients. The new program, dubbed Combinatorially Designed Metallo-Pharmaceuticals (CDMP) is designed to generate focussed customized collections of metallo-compounds rapidly and efficiently to enable new products to be brought to the market faster and more cost effectively than is currently possible.
According to Resolution CEO John Thornback, his firm is the first to apply combinatorial chemistry techniques to the field of metal containing drugs. "We developed and implemented CDMP for our in-house programs, but we quickly realized that the technology could be applied to a much wider range of applications. With CDMP, we are able to generate large numbers of metal compounds rapidly and in a form suitable for biological evaluation. We believe CDMP has the potential to identify completely new classes of compounds with potential to treat and diagnose cancer, arthritis and heart disease.
"For our purposes, we define metallopharmaceuticals as drugs containing a metal as an integral part of the drug. Metallopharmaceuticals can be traditional drugs like cisplatin, metal-containing contrast agents, or radiopharmaceuticals. It doesn't matter if the metal is an integral pharmacologic agent [as in cisplatin], or, in the case of radiopharmaceuticals, an imaging or radiotherapy agent."
Resolution's combinatorial techniques appear to work as readily with metal-containing pharmaceuticals as with traditional organic-only drugs. Parallel synthesis also facilitates screening of metal-containing compounds just as easily as traditional drugs. "Combinatorial chemistry is a powerful technique for developing receptor-based drugs," Thornton told DrugDiscovery Online. "Traditionally, metal-based drugs are screened after the binding experiments and bioassays are completed. In other words, the testing is done on something other than the final product. We've developed technologies that enable us to make libraries of the metal-containing compounds, and then screen them with the metal in place."
With its pharmaceutical industry clients, Resolution will prepare focussed libraries of metal compounds in formats suitable for biological evaluation. The company may also, at the request of the client, conduct biological screening and complete product development of the lead compounds.
Most of Resolution's radiopharmaceuticals contain short-lived radioisotopes with an imaging or therapeutic function. The non-metal part of the compound allows targeting to specific organs or biochemical functions in the body. Resolution's RP128 is in Phase II clinical trials for imaging sites of inflammation diseases such as Crohn's disease, osteomyelitis, and rheumatoid arthritis. RP527, Resolution's lead product from its oncology program, is expected to begin Phase I/II clinical trials in Europe shortly for use in the diagnosis and imaging of a number of common cancers.
Technicium Agent in Clinical Trials
The current interest in the radiolabeling of biologically important molecules with Tc-99m stems from the desire to develop a target-specific diagnostic radiopharmaceutical. Several techniques have evolved for labeling target molecules with technicium, the best of which use a bifunctional chelator. The final steps in the labeling procedure are attaching the chelator to a targeting molecule and then labeling the conjugate. Another method is labeling the chelator first and then coupling it to the targeting molecule. RP414 has been used successfully in both methods.
Resolution's bifunctional chelation technology is based on the tetrapeptide RP414, which is an excellent chelator for both Tc and Re. The dimethylglycine, serine, and cysteine residues of RP414 coordinate to Tc or Re to form stable, water-soluble complexes. The last glycine residue acts as a linker and can attach the peptidic chelator to biological molecules. RP414 has been successfully attached to peptides, proteins, and small molecules using standard coupling techniques. In addition, the chelator can be built onto biologically important peptides on a peptide synthesizer. The chelation/coupling techniques have been patented by Resolution, and the complex's efficacy in imaging is now being tested in Phase I and II clinical trials.
For further information on Resolution: John Thornback, CEO, Resolution Pharmaceuticals Inc., 6850 Goreway Dr., Mississauga, Ontario L4V 1V7, Canada. Tel: 905-677-0831. Fax: 905-677-9595. Email: jthornbk@respharm.com.
By Angelo DePalma