New Drug Innovations Enabled by Cutting Edge Chemistry

Of all the innovations to have an impact on modern society, the novel drugs developed over the past 60 years have perhaps had the biggest impact.

New Drug Innovations Enabled by Cutting Edge Chemistry

Innovations in the novel drugs developed over the past 60 years have had one of the largest impacts on modern society. From contraceptives and antidepressants to antivirals and cancer therapies, drugs have dramatically improved our health and wellness. There have been numerous breakthroughs as pioneering treatments for human illness were discovered, developed, and commercialized. In recent years, however, true innovation in drug development measured by new molecular entity approvals has slowed, and throwing ever increasing amounts of money into R&D has not helped. In fact, the number of new drug approvals per billion dollars spent has decreased exponentially since 1950.1 Industry critics point to a shift in focus away from discovering new cures toward “me-too” drugs, the aggressive pursuit of life cycle management strategies such as reformulation, 2 and an increasing role of mergers and acquisitions to bolster or even replace a company’s R&D efforts.

Do these criticisms mean that innovation in pharma is dead?

A Fundamental Science Perspective

Scientists in the field have their own ideas about what needs to change to get pharma back on the path to innovation. They acknowledge that mergers have had an impact on their ability to innovate,4 but there is more to the story when you get down to a molecular level. Many technological advances in the way drug discovery is done have come and gone, leaving both positive and negative effects. As it turns out, one technology that held promise to accelerate innovation came with a price that has only recently been recognized.

The use of high-throughput screening for drug discovery started in the mid-1980’s and expanded significantly in the 1990’s. It seemed a miracle: discovery programs could investigate the activity and properties of new compounds at a rate hundreds of times faster than was possible before. Finding or synthesizing new compounds became the rate-limiting step. To keep up with the pace at which compounds could be screened, medicinal chemists started employing parallel synthesis and combinatorial chemistry to maximize their compound throughput, and in the process amassed vast libraries of compounds in the millions. Despite this feat, the success rate in the clinic continued to decline.

Looking back, many experts in the field agree that the combinatorial chemistry approach caused a downtick in the amount of structural diversity medicinal chemists were generating, and the vast compound libraries that resulted from those efforts were quickly exhausted on a limited number of therapeutic targets.5

Many chemists in both academia and the pharmaceutical industry believe that in order to enhance the efficiency of drug discovery endeavors, medicinal chemistry programs need to start generating structural classes of compounds overlooked by the HTS-driven approach.6 To access these novel classes of structures, new synthetic tools are necessary, and olefin metathesis is among the reactions with the potential to unlock new frontiers in chemical space.7 One successful example of such a novel compound class is described below.

Innovator Spotlight: Aileron Therapeutics

Even as our understanding of disease has grown over the past decades, existing approaches still can’t be used to reach many important therapeutic targets. For instance, the modulation of intracellular protein-protein interactions (PPIs) holds promise in many indications but remains elusive for traditional small molecule agents.

In the mid-1990s, academic researchers discovered a new class of compounds called stapled peptides that could mimic the specificity of PPIs while maintaining the stability and permeability of small molecules. While the compounds had promising activity against PPI targets, synthesizing them proved extremely difficult using traditional methodologies.

Grubbs Catalyst® technology was the key. While different approaches were attempted, Materia’s metathesis catalysts were the first to efficiently and reproducibly deliver successful syntheses of stapled peptide structures.8

By 2007, the therapeutic potential of stapled peptides had been validated in the lab,9 and a new company, Aileron Therapeutics, was created for further development and commercialization. Over time, Aileron attracted significant interest from major pharmaceutical companies and by 2009, it had raised $40 million from the venture funds associated with GlaxoSmithKline, Novartis, Eli Lilly and Roche. More recently, Aileron entered human clinical trials and signed a $1.1 billion deal with Roche. Materia is excited to continue to support Aileron’s groundbreaking innovation and looks forward to the bright future for its new therapeutics.

A Brave New Future in Innovation

Today’s regulations, markets, and technology present challenges to the pharmaceutical industry — but also opportunities for committed innovators. Stapled peptides are only one of many novel compound classes that may grant success where so many others failed. Boldly exploring the chemical space made accessible by Grubbs Catalyst technology has already resulted in approved treatments for HCV and chemotherapy-induced vomiting,10 and countless possibilities await those willing to step beyond familiar chemical space.11

For more information on Materia’s Grubbs Catalyst technology and how we work with our customers to meet their needs for enabling synthesis solutions, contact us directly.

1 Scannell, J. W.; Blanckley, A.; Boldon, H.; Warrington, B. “Diagnosing the decline in pharmaceutical R&D efficiency” Nat. Rev. Drug Disc. 2012, 11, 191.

2 Gibson, Shannon. "The Use and Abuse of Drug Reformulation in Pharmaceutical Life Cycle Management: A Comparison of the Market Defence of Tricor in the US and Lipidil in Canada." Health LJ 2013, 20,107.

3 Fisher, N.; Liebman, S. “Are M&A Replacing R&D in Pharma?” Forbes, April 22, 2015.

4 LaMattina, J. L. “The impact of mergers on pharmaceutical R&D.” Nature 2011, 10, 559.

5 Barker, A.; Kettle, J. G.; Nowak, T.; Pease, J. E. “Expanding medicinal chemistry space” Drug Discovery Today 2013, 18, 298.

6 Lovering, F.; Bikker, J.; Humblet, C. “Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success.” J. Med. Chem. 2009, 52, 6752.

7 Brown, D. G.; Bostrom, J. “An analysis of past and present synthetic methodologies on medicinal chemistry: Where have all the new reactions gone?” J. Med. Chem. 2015.

8 Schafmeister, C. E.; Po, J.; Verdine, G. L. “An All-Hydrocarbon Cross-Linking System for Enhancing the Helicity and Metabolic Stability of Peptides” J. Am. Chem. Soc. 2000, 122, 5891.

9 Walensky et al “Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix” Science, 2004, 305, 1466.

10 (a) Horvath, A. et al. Improved process for preparing an intermediate of the macrocyclic protease inhibitor TMC 435. PCT Int. Appl. 2013061285, May 2, 2013. (b) Wu, George G. et al. “Process and intermediates for the synthesis of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds ”WO 2010028232, Mar 11, 2010.

11 (a) Doak, B. C.; Zheng, J.; Dobrizsch, D.; Kihlberg, J. “How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets” J. Med. Chem. 2015, (b) Lowe, D. “One Step Beyond! Maybe More.” Science Translational Medicine: In the Pipeline Nov. 10, 2015.