Medicinal Chemistry

At the Merck Frosst Centre for Therapeutic Research, chemists in the Organic Chemistry department work closely with the scientists in the Biological Sciences department. Together, they study the behavior of biological systems and interesting molecular classes, to find the piece that fits into the therapeutic puzzle. In this exploratory period, organic chemists hand-craft a variety of compounds or select them from the sample collection. Molecules that show promise as potential drug candidates are assayed, redesigned, and assayed again in a continuous feedback loop with Biological Sciences until a compound suitable for safety testing is identified.

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The team holds the key to designing good drug candidates-a world-class understanding of the forces that bind small molecules to macromolecules like proteins and enzymes. In 1979, when it became clear that leukotrienes could not be obtained from biological sources, it fell to Organic Chemistry to synthesize them. Then, using leukotriene D-4 (LTD-4) as a tool, the organic chemists were able to probe the affinities for the receptor by modifying the natural ligand until the most critical structural features for binding were identified. Then, with this information in hand, a leukotriene blocker had to be developed. Using state-of-the-art organic synthesis, the team prepared and identified blockers, or antagonists, in the low nanomolar potency that closely mimicked the interaction of LTD-4 with its receptor. The drug candidates validated the hypothesis that LTD-4played a crucial role in triggering asthma. Finally, in 1991, the organic chemists at Merck Frosst synthesized the first molecule of SINGULAIR ^®(montelukast sodium).

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Work with leukotrienes led to the discovery of caspases, enzymes that induce apoptosis when activated. The hunt is now on to design inhibitors of caspases that can cross the blood-brain barrier to prevent apoptosis that kills brain cells following stroke. To develop and optimize the molecule, the team uses state-of-the-art combinatorial chemistry, traditional synthesis, x-ray analysis and molecular modeling.

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