Some thoughts on small molecule drugs of the future and attendant synthetic challenges…..

Blog April 2014 – Andy Wells, Charnwood Technical Consulting

It is interesting to follow the debate on small molecule API’s vs. biologics. In my view, the demise of small molecule API’s has been overstated , and moving forward, small molecules will have an important place alongside monoclonal antibodies, conjugates, vaccines , therapeutic enzymes and peptides in the fight against disease and maintaining wellbeing for mankind. The drop in the number of new molecular entities launched over the past 10 years or so, the ‘poor’ return on investment in pharma R&D has been extensively debated elsewhere, along with a myriad of suggestions to improve the success rate in small molecule research. As a scientist with an interest in developing greener and more sustainable chemical manufacturing technology, I believe that we should not only look at present and past challenges, but also look forward to the molecules of the future to ensure that we focus our chemistry toolboxes to meet future needs. Discussed below are some thoughts and synthetic challenges (by no means a comprehensive set) for pharmaceutical synthesis in 2020, illustrated by some recently launched molecules, or in mid/late phase clinical development.

Molecular complexity

Anyway, so we expect to see more complex structures – more saturated heterocyclic rings, fused rings, spiro systems, more chirality etc. Is more molecular complexity a necessity for success in the clinic? Well, not necessarily. Some small molecules can have big effects in biological systems – O2, NO, CO2, CO, HCN, H2S are well known –it surprised me to discover recently that Xenon is an effective and powerful general anaesthetic.

It can be seen from some recent launches, PIrfenidone, dimethyl fumarate and vortioxine –see below, that molecules with surprising ‘simple ‘ structures still get through. The 2013 prize for the simplest molecule launched has to go to dimethyl fumarate. As a point of interest, dimethyl fumarate has recently been banned in the EU under REACH legislation as an anti-fungal treatment for leather goods due to a number of severe chemical sensitization cases.


Thankfully as synthetic chemists who like a challenge, there are molecules coming through that will test our skills in assembling the molecular architecture and essential molecular decoration – see structures below. It has to be noted that any change in the small molecule portfolio is slow and evolutionary rather than revolutionary. Some new hetero-aromatic and saturated heterocyclic ring systems are coming through discovery into development. Contrary to popular belief, the number of chiral compounds being launched does not really seem to be increasing. The figure seems to be fairly constant at around 50% with the rest being achiral molecules with the occasional racemate. What does appear to be subtlety changing is the nature of chiral compounds. These seem to be polarising into molecules that have either one or multiple chiral centres, with fewer in the two to three chiral centre range figure 1. Drugs with five to eight chiral centres have never really been popular, falling into the region where natural products and synthetic chemistry don’t deliver/fear to tread.


Figure 1 V2020 Analysis of chiral compounds IN Organic Process R&D journal –number of molecules with X chiral centres vs. year.

A quick look at some of the molecules featured here will confirm the importance of chemical methodologies directed towards making complex chiral molecules.


The number of fluorinated small molecules entering the market varies from 14-35%, averaging ~25%,demonstrating the critical importance of fluorine chemistry to the industry. Typically aryl and heteroaryl fluorides have predominated, alongside trifluoromethyl groups. This pattern appears to be changing, with a more diverse set of aliphatic carbon – fluorine bonds appearing – see below.



Although much less prevalent than Fluorine, the patterns of use of Bromine and Iodine are changing.

Often introduced as synthetic handles to impart certain reactivity or selectivity, and then removed during chemical transformations, the number of molecules retaining Bromine and Iodine in the final drug substance are slowly increasing – see some examples below.


Reactive pharmacophores

The number of API’s with reactive pharmacophores is increasing – two are shown below –ibrutinib and carfilzomib. Dimethyl fumarate would also fall into this category. These molecules are typically irreversible enzyme inhibitors acting by forming covalent bonds between essential amino acid residues in an enzyme active site and an alkylating or Michael acceptor group.


Natural products

Finally, each year one or two new drugs still enter the market that have their genesis in natural products. A good example is carfilzomib, based on epoxomicin – a naturally occurring selective proteasome inhibitor-structure below.


Blog January 2014 – John Blacker, iPRD, University of Leeds

Since Sir Geoffrey Wilkinson invented a rhodium catalyst selective for the hydrogenation of cis-alkenes,1 the last several decades have seen an extraordinary rise in the use of precious metal-based catalysts. Soluble forms of palladium, platinum, gold, rhodium, iridium, ruthenium have been made with organic ligands that control the metal, and its environment, to facilitate chemo-, regio-, stereo- and selective chemical transformations. As a result of this, some of these catalysts have found application in the production of complex organic chemicals; but importantly, also because ways have been found to use them efficiently, either through high turnover, or recovery and recycle. Despite this the majority of precious metal catalysts, identified by a large number of academic groups throughout the world, are unusable, even in the high value pharma industry. This is because: the loadings are too high with consequent cost (anything above 0.1mol% is usually uneconomic, whilst most report 1-10mol%); recovery and recycle is frequently impractical. Furthermore these metals are toxic to biological systems with regulations that stipulate drug products must contain <10 ppm quantities.

The increasing global consumption of precious metals has raised international concern over their medium to long-term supply. Whilst by far the largest consumers are the automotive and electronics industries, the pharma industry is involved and needs to adopt sustainable precious metal use policies. This should include some of the Green Chemistry Principles around avoidance, higher efficiency, recovery and recycle.2 The Chem21 project is working to support these aims by evaluating the use of alternative organo-, bio- and base metal catalysts as well as more efficient processes and recovery recycle methods.

The recent Winter Process Conference held by iPRD,3 and organized by Scientific Update had a number of talks from Chem21 collaborators, setting the scene by covering new base-metal catalysts and applications in atom-efficient transformations. Prof. Beller form LIKAT, Rostock spoke, amongst many exciting developments, of new iron catalysts for chemoselective nitroaromatic-reductions;4 Dr Kai Rossen of Sanofi-Aventis spoke of their clean photocatalytic oxidation process in Artemisinin production;5 Prof. Bert Maes of University of Antwerp  spoke of their work on the use copper catalysts in aromatic C-H activations;6 I spoke of the Chem21 work done by Dr Andy Wells and Dr John Hayler and others in analyzing the impact of green chemical approaches over the last decade, gaps and areas of future concern including precious metal catalysts.

A paper recently published rather depressingly concludes that finding alternatives to precious metals is unlikely.7 Whilst this may be true regarding the material properties of these metals, with catalyst applications there are already some base metal alternatives and more are being reported every week in what has become an intensive area of research.

A further caution against a knee-jerk response in abandoning precious metals in catalysis, is that their availability follows standard supply and demand economics. As demand outstrips supply and prices increase, new mines become economic and prices can then fall. This recently happened with rhodium that became very expensive until a new gold seam was opened in which there was a higher abundance of the rhodium side-product.8 Despite refining more metals, the conservation of matter laws dictates that they don’t disappear, rather they change form. Consequently more effort needs to be put into identifying methods for recovering metals from catalytic converters, mobile phones and the like. Better still to design such products with recovery in mind. Likewise the community should design methods for catalyst separation and recovery from the outset. Chem21 is working to develop catalyst immobilization methods with partners Reaxa Ltd, and membrane separation methods, Vito Ltd.

To conclude, we should be cautious in redirecting research to sustainable catalysts, not to ignore the amazing progress made in using precious metal catalysts, but to find ways of using these more effectively to make products economically, safely and sustainably. Nevertheless the whole community should welcome the progress being made in new organo-, bio- and base metal catalysts which will give process chemists better alternatives to realize more sustainable and cost effective drug manufacture.

  1. Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G., Journal of the Chemical Society A, 1711–1732, 1966.
  2. Kletz, T.A., Chemistry and Industry, 287–292, 1978; Anastas, P. T., Warner, J. C., Green Chemistry Theory and Practice. New York: Oxford University Press, 1998
  4. R. V. Jagadeesh, A.-E Surkus, H. Junge, M.-M. Pohl, J. Radnik, J. Rabeah, H. Huan, V. Schünemann, A. Brückner, M. Beller, Science, 29 November 2013: 1073-1076
  5. A. Burgard, M. P. Feth, K. Rossen, EPAppl. 2660234 A1, 20131106
  6. J. De Houwer, K. Abbaspour Tehrani, B. U. W. Maes, Angew. Chem. Int. Ed. Engl., 51, 2745, 2012
  7. Recycling of (critical) metals, G. Gunn, C. Hagelüken, Published Online: 27 DEC 2013, DOI: 10.1002/9781118755341.ch3