Medicinal Chemistry

Parallel synthesis in solution is a technique used in the drug discovery program at Merck Frosst to rapidly synthesize a large number of compounds. It has had a tremendous impact on the way Merck Frosst designs and refines new drug candidates. The technique is growing in importance throughout the pharmaceutical industry because it uses the core expertise of medicinal chemists -namely, doing chemistry in solution.

The approach of using robotic systems to carry out tedious tasks such as weighing samples, extraction and purification allows chemists to concentrate their efforts on more defined targets, and thus increases the diversity of the selected molecules.

Developing the custom-designed system involved collaboration between several departments within Merck Frosst, when it became clear that the necessary robotics were not available from commercial sources. The system was designed to the high levels of complexity needed to handle a wide range of compounds, including organic solvents and aqueous solvents such as brine, strong acid and base.

The team also developed unique software to manage all the reactions from a given library on behalf of the chemist. The software also communicates with several commercial systems, such as a weighing station, a liquid handler and an LC-MS HPLC purification system. In addition, Merck Frosst has developed collaborations with robotics companies worldwide to expand the application of the technology, which is undergoing constant development to broaden the range of procedures that it can handle.

The benefits of automated parallel synthesis go beyond timesaving. Although the technique can increase the output of new analogues 10 to 20-fold or more, crucially it also optimizes the discovery process. It does this by presenting chemists with a broader range of compounds, which would not have been evaluated in a traditional structure-activity relationship (SAR) process.