Opinion | Published:

Expanding the medicinal chemistry synthetic toolbox

Nature Reviews Drug Discovery volume 17, pages 709727 (2018) | Download Citation

Abstract

The key objectives of medicinal chemistry are to efficiently design and synthesize bioactive compounds that have the potential to become safe and efficacious drugs. Most medicinal chemistry programmes rely on screening compound collections populated by a range of molecules derived from a set of known and robust chemistry reactions. Analysis of the role of synthetic organic chemistry in subsequent hit and lead optimization efforts suggests that only a few reactions dominate. Thus, the uptake of new synthetic methodologies in drug discovery is limited. Starting from the known limitations of reaction parameters, synthesis design tools, synthetic strategies and innovative chemistries, here we highlight opportunities for the expansion of the medicinal chemists' synthetic toolbox. More intense crosstalk between synthetic and medicinal chemists in industry and academia should enable enhanced impact of new methodologies in future drug discovery.

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Acknowledgements

G.M.K. is supported by the National Brain Research Program (2017–1.2.1-NKP-2017-00002) of the National Research, Development and Innovation Office, Hungary.

Author information

Affiliations

  1. Medicinal Chemistry, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

    • Jonas Boström
  2. Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Waltham, MA, USA.

    • Dean G. Brown
  3. NCE-Medicinal Chemistry, GlaxoSmithKline R&D, Stevenage, Hertfordshire, UK.

    • Robert J. Young
  4. Medicinal Chemistry Research Group, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.

    • György M. Keserü

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Competing interests

The authors declare competing interests: see Web version for details.

Corresponding author

Correspondence to György M. Keserü.

Supplementary information

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Glossary

Chemical space

Chemical space is a nebulous term used in various ways, but pertinent to drug discovery, it is the classification of molecules in terms of their physicochemical make-up, such as size, shape, lipophilicity, charge and hydrogen-bonding potential, which together can be used to describe the chemical space occupied.

Design–make–test–analyse (DMTA) cycle

The iterative central process in lead optimization, involving a cycle of four steps: design (a hypothesis is constructed to improve the profile of the lead molecule); make (compounds exemplifying the design are synthesized); test (synthesized compounds of confirmed structure and purity are tested in one or more carefully constructed and controlled assays); and analyse (the experimental data are analysed, and the results are used to amend a design hypothesis for the next cycle).

Drug-like compounds

Drug-likeness is another term that is used in various ways, often to describe the possession of physicochemical properties that are typical of orally absorbed small-molecule drugs. Lipinski's rule of five (Ro5) is one common metric; if no more than one of the following criteria is exceeded, then there should be a reasonable chance of oral bioavailability: molecular mass <500 Da, cLogP <5, number of hydrogen-bond donors <5 and number of hydrogen-bond acceptors <10. More recently, it has been demonstrated that oral activity is feasible beyond Ro5, and these programmes follow specific principles that contribute to the oral bioavailability.

Fragment

A simple, small and relatively polar molecule with 8–17 heavy atoms, often screened using sensitive biophysical techniques (such as X-ray crystallography, NMR spectroscopy and surface plasmon resonance) to identify inherently weak binders that can be elaborated into lead compounds.

Functional group tolerance

The range of organic functionalities that do not react with or impede the reagents and/or catalysts involved in a transformation. As drug molecules are predisposed to contain charged or hydrogen-bonding motifs to, for example, achieve potency and selectivity, this can often cause issues and interfere with catalysts, ligands and reactive partners.

Lead-like

Lead-likeness is a term that describes an aspirational profile for a screening collection of molecules that have physicochemical properties, together with predicted safety, pharmacokinetic and pharmacodynamic data and complexity, that bridge fragment space and drug-like space, as well as appropriate chemical functionalities that can be used in the optimization of the molecules into candidate drugs.

Quality of drug candidates

Like chemical space, the notion of compound quality is used in various ways, but physicochemical parameters can predict the likely quality of a compound, in conjunction with pharmacokinetic and pharmacodynamic data, giving confidence in probable exposure, efficacy and safety. This should not be prescriptive, but more optimal properties indicate a higher likelihood of success. Note that the actual set of physicochemical parameters is dependent on the target, the compartment where the target is engaged and the route of administration.

Robust reactions

Reproducible chemical transformations applicable to structurally diverse substrates, tolerating a range of functionality and able to be realized on simple equipment in a reasonable time period. Factors for robust reactions for medicinal chemistry include the following:

• Provide structures relevant for drug discovery

• Technically straightforward (no special equipment needed)

• Moderately sensitive to reaction parameters

• Broad applicability (also with polar substrates)

• Broad availability of starting materials and reagents

• Broad functional group tolerance, including polar functionalities

• Time for delivery of the target compounds is reasonably short (<1 month ideally)

• Simple operational procedure (minimal training and support needed)

• Low-risk reagents to comply with often onerous local safety rules

A full-size poster depicting the set of most popular robust reactions (available online for downloading; see Supplementary Fig. 1) illustrates their impact on drug discovery. Our hope is that displaying this poster in offices and laboratories could highlight the importance of expanding the medicinal chemistry synthetic toolbox and stimulate debate.

Structurally diverse substrates

The breadth of diversity of a given reaction type is dependent on the accessibility and intrinsic reactivity of the substrates and/or building blocks involved in the reactions. A reaction that can use a number of different reactive groups can be advantageous to medicinal chemists, as it will allow access to more analogues.

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DOI

https://doi.org/10.1038/nrd.2018.116