Nick Terrett was educated at the University of Cambridge (MA, Ph.D.). During his extensive career, Nick has worked as a drug discovery chemist and manager in both the pharmaceutical and biotech sectors. Among many notable career achievements, Nick was lead chemist and inventor for the program that discovered sildenafil citrate (Viagra) at Pfizer. Nick currently serves as Scientific Associate Vice President and European Chemistry Lead for Merck Sharp & Dohme. His most recent publication, "The importance of synthetic chemistry in the pharmaceutical industry," appears in the January 18, 2019 edition of Science.
It's obvious that the pharmaceutical industry needs advanced capabilities in synthetic chemistry for drug discovery and development. New molecules usually don't make themselves—rather they are the cumulative end-product emerging from an intricate process of hypothesis, design, and synthesis. Despite great strides in in silico testing, we still need to make individual molecules and test what they do in biological systems—whether those are petri dishes or patients. Chemical synthesis is the skill set at the heart of discovering new drug molecules. The pharmaceutical industry employs thousands of chemists who craft compounds by a complex and carefully planned step-by-step synthetic process—making original molecules from available precursors.
However, it's now being recognized that synthetic chemistry also contributes to innovation in drug design, going beyond the quotidian process of just being a means to an end, and instead having a creative role in drug discovery. In the same way that new building techniques have fired the imagination and creativity of architects, new chemical reactions and synthetic transformations can inspire drug design. Paradoxically, it's regrettably true that many pharmaceutical companies have reduced commitment to synthesis, viewing the field as not essential for innovation in drug discovery.
Within MSD (Merck & Co., Inc., Kenilworth, New Jersey, U.S.A.) and in contrast to the actions of many other pharma companies, we promote innovation in synthetic chemistry as being critical to success in drug discovery and development. Furthermore, new developments in synthetic methods, biocatalysis, chemoinformatics, and reaction miniaturization empower the speed and quality of discovery. Our thoughts in this area have been summarized recently in a review in Science.
Synthetic methods and common chemical precursors define the "chemical space" that can be efficiently explored to find molecules that progress to drug candidates. Overreliance in the past on just a few reliable synthetic reactions (e.g., amide bond formation, cross couplings, and nucleophilic substitution reactions) has biased many drug discovery programs resulting in limited structural diversity. And in some cases, an absence of reasonable synthetic routes has limited or even prevented biological evaluation of some chemical space.
In contrast, innovative synthetic methods can transform drug discovery, by giving access to biologically-active and structurally intricate molecules in a cost-effective manner. To give one early example, the synthesis of beta-lactam antibiotics was revolutionized by using carbenoid N-H insertion chemistry. Prior to this, synthetic challenges prevented assessment of related antibiotics that might exhibit novel activity. Synthesis-enabled design opened up paths to previously unattainable therapeutically significant molecules.
In recent years, the Nobel Prize has recognized novel synthetic methodologies including asymmetric hydrogenations and epoxidations, palladium-catalyzed cross couplings and ring-closing metathesis, and these have enabled new directions in drug design. Medicinal chemists have relished use of methods that control reactivity in complex, drug-like molecules, and open up novel chemical space.
And growth in synthetic innovation continues. One expanding area of synthesis employs visible light photoredox catalysis for a range of mild chemical transformations. For example, the direct trifluoromethylation of heteroarenes has been adopted broadly in the pharmaceutical industry due to wide functional group tolerance in addition to the activation of non-conventional bonds in drug-like molecules.
Synthetic chemistry breakthroughs provide inspiration for discovery and development of medicines with important therapeutic value. Despite recent advances, molecular design is still limited due to unsolved problems in synthesis. Much more needs to be invented, such that synthetic chemistry will never restrict compound design or the speed of drug discovery, as well as inspiring access to uncharted chemical space. Examples of key unsolved synthetic problems include selective saturation and functionalization of heteroaromatics, concise synthesis of highly functionalized, constrained bicyclic amines, and highly controlled C-H functionalization in complex molecules.
At MSD we believe that collaboration between the pharmaceutical industry and leading academic groups in the field is essential to innovate new and disruptive synthetic chemistry. One of the most fascinating ideas to emerge recently is the notion of 'molecular editing', where one could insert, delete or exchange atoms in highly complex compounds in an entirely selective manner.
Structural editing is an aspirational goal, but not impossible given the push for transformational synthetic chemistry. MSD along with many other pharmaceutical companies continues to work closely with academic chemists in devising new solutions for synthetic challenges that will enhance, accelerate, and inspire drug design in the future.
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