Pyridynes Provide Access to Drug-Like Compounds
Medications intended to treat innumerable disorders and diseases are introduced into the market on a regular basis, but the process of drug discovery is long and limited by the tools at a chemist’s disposal. This often amounts to the types of chemical reactions chemists are able to run to build new molecular structures that could potentially become drugs.
Many commercially available drugs contain organic molecules known as heterocycles, and one of the most common heterocycles prevalent in drugs is called the pyridine ring. Over 100 medications on the market today include pyridine rings, such as Lunesta, commonly used to treat insomnia, Actos, commonly used to treat Type II diabetes, Nexium, commonly used to treat acid reflux, and Singulair, commonly used to treat asthma. By making compounds called "pyridynes," Professor Neil Garg and Adam Goetz, a Ph.D. candidate in Garg’s laboratory, have introduced a new tool to allow chemists to construct various molecular structures that can potentially aid in future drug discovery. This research was published online in Nature Chemistry on November 25.
"You need basic chemistry to be able to access potential drugs, and we think this is a very useful tool that drug companies will be able to use to make new chemicals that they have not been able to make before," Garg said.
Pyridine rings consist of six atoms that can be numbered for classification purposes. Garg and Goetz wanted to introduce new arrangements of atoms, or substituents, on pyridine rings in a controlled process, in order to form new molecular structures to aid chemists in drug discovery. They aimed at producing 3,4-pyridynes, in which the third and fourth atoms in a pyridine ring are attached to one another by a very reactive triple bond. "The high reactivity of the pyridyne allows for many possible chemical reactions," Garg said.
Although chemists have been producing these types of pyridynes for over 30 years, Garg and Goetz recognized some limitations in their methods, as they were not user-friendly, not often used in drug discovery, and were more likely to result in two, rather than one, product, which is not helpful to those trying to make very specific compounds. To simplify the process, Garg and Goetz prepared "pyridyne precursors," which are stable chemicals that can be stored in bottles. Pyridyne precursors can be put into chemical reactions to be converted into pyridynes. They can then be used to quickly react with another ingredient, which can be chosen by the researcher, to form a new product. Since the last ingredient will vary in different reactions, according to a chemist’s preference, many new substituted pyridines can be made.
Garg compared chemical reactions and the process of making substituted pyridines to preparing a meal, in which ingredients are added to a pot to produce a flavorful product. "You can think of pyridynes as being the key flavors that come out when ingredients are simmering together," Garg said.
Garg and Goetz are currently focused on making their pyridyne precursors commercially available. A leading chemical supplier has already purchased three compounds to test market viability, the first step toward drug companies widely using pyridynes in drug discovery.
"There’s a popular quote by one of the former directors of the National Institutes of Health, and he said that the No. 1 stumbling block in drug discovery is synthetic organic chemistry," Garg said. "I think a lot of industrial researchers agree. We’re good at synthetic organic chemistry, but we will always need new ways to build molecules, and new ways to build molecules that have never been made before. Our pyridyne chemistry is a contribution along those lines."
