Plenary Lecture 1

Title: Medicinal Chemistry, quo vadis? A personal view backwards on successful drug discoveries within the changing climate of pharmaceutical R&D

Dr. Helmut Buschmann

Research, Development & Consulting GmbH (RD&C), Austria

Lecture Summary:
Today’s innovative drug discovery is costly and time consuming, with very few novel therapeutics making it to the market place. The enterprise of drug discovery and development is fundamentally shifting in the last decade. Dramatic and irreversible changes are reshaping the roles of the pharmaceutical, biotechnology and academic areas and consequently also the role medicinal chemistry.1

            Over the past decade, scientific and business needs have driven the pharmaceutical industry to more closely align drug discovery and drug development efforts.2 The general view is that the process whereby future drugs are discovered and developed will be fundamentally different to how these activities were performed in the past.3

            Traditional medicinal chemistry approaches adopted during the 1970s and 1980s were focused primarily on analoguing of endogenous ligands and industry leads, moving from in vivo models to a single target selective drug for a single mechanism. Following the lock and key model proposed by Ehrlich more than a century ago, over the previous decades, drug discovery efforts have focused on identifying single selective drugs that target a single mechanism; that is, identifying ligands (‘keys’) that fit into specific targets (‘locks’). Achieving target specificity of active compounds has, for at least three decades, been considered a hallmark of drug discovery efforts, as a consequence of an increasingly sophisticated molecular approach to discovery, primarily focusing on isolated targets and specific binding assays.4

            Chemistry was low throughput and done iteratively, driven primarily by biochemical observations derived from animal testing. In contrast, the past decade has witnessed an evolution in medicinal chemistry approaches wherein automation has been effectively utilized in the synthesis of large numbers of analogues (combinatorial chemistry) and in the rapid screening of large numbers of compounds (HTS). At the turn of the century, subsequent to identification and characterization of large numbers of targets, the deciphering of the human genome led to an explosion in the “-omics” technologies.5 The assimilation of the resulting information and correlation of potential therapeutic targets with human diseases present tremendous challenges for drug research.6

            The development of multi-target drugs experienced a renaissance during the past decade. Small molecules which interact with more than one target seem to be a very attractive to address various diseases. The postulated advantages include better efficacy coming along with less unwanted side effects and a simpler pharmacokinetic profile compared to a combination of two or more selective drugs. In addition, medicinal chemists now routinely impart a targeted effort to incorporate drug-like properties into their chemical scaffolds, with the prevailing goal of not only identifying a compound that can advance into development, but also identifying an associated solid state phase that has appropriate physicochemical characteristics that allow for optimal in vivo performance. A recent trend in drug discovery has been to view the process of drug design as a multi parameter optimization problem, in which, from the beginning, a project team attempts to identify drug candidates that achieve an optimal balance of the biological and physicochemical properties required for a chosen therapeutic objective.6

            A personal view backwards based on successful drug discoveries will be presented within the changing climate of pharmaceutical research and development strategies and technologies.


Acknowledgments: I thank my colleagues and co-workers from Grünenthal GmbH (Aachen), Laboratorios Dr. Esteve (Barcelona), Savira Pharmaceuticals GmbH (Vienna), AiCuris Anti-infective Cure GmbH (Wuppertal) and Research, Development & Consulting GmbH (RD&C, Vienna), who provided insight and expertise that greatly assisted the research.


References: [1] Abou-Gharbia, M.; Childers, E. C. J. Med. Chem. 2013, 56, 5659.

2 Abou-Gharbia, M.; Childers, E. C. J. Med. Chem. 2014, 57, 5525.

3 Kleemenn, A. Pharm. Ind. 2013, 75, 562.

4 Kinch, M. S.; Kinch, S. L.; Hoyer, H. Drug Discovery Today. 2014, 19, 1033.

5 Waring, M. J. et al. Nature Reviews Drug Discovery 2015, 14, 475.

6 Tsukamoto, T. ACS Med. Chem. Lett. 2013, 4, 369.