Drugs in middle space

Nick Terrett

Nick Terrett is Chief Scientific Officer for Ensemble Therapeutics Corp, a biotech company in Cambridge, MA, using novel chemistry technology platforms to explore and optimise macrocycles for drug discovery. He is interested in the potential of drug-like macrocycles to address challenging disease-relevant protein–protein interactions.

David Rees

David Rees is Senior Vice President of Medicinal Chemistry at Astex Pharmaceuticals, Cambridge UK, and serves on the editorial board of MedChemComm and is the President of the Organic Division of the Royal Society of Chemistry. He is a co-inventor of the launched drug sugammadex whose molecular weight (2178 Da) makes it an example of a ‘middle space’ drug.

The publication in 1997 of a paper¹ that described guidelines for drug permeability had an impact that was disproportional to the conservative language employed by its authors. Lipinski's paper first outlining the ‘Rule of 5’ suggested that poor absorption or permeability would result if compounds exceeded clearly defined hydrogen-bond counts, molecular weight (MW) or lipophilicity (log D). For the pharmaceutical industry struggling with drug discovery failures due to poor pharmacokinetics, and also contending with numerous hits of uncertain quality emerging from newly established high throughput screening (HTS) systems, these simple and serviceable guidelines for drug design were rapidly adopted.

Although the ‘Rule of 5’ was a suggestion based on empirical observations for which many exceptions and exemptions were possible, it was obsessively applied throughout the pharmaceutical industry. One particular consequence was a reluctance to contemplate investigation of any drug molecule with a molecular weight exceeding 500 Daltons. Medicinal chemistry labs avoided making such compounds, and they were black-listed or even removed from HTS sample files.

Small molecule research has been a highly successful drug discovery philosophy. However the last ten years has marked a sea-change in which there has been an inevitable shift to more challenging pharmaceutical targets. Advances in molecular and cell biology have revealed a wealth of biochemical mechanisms underlying poorly treated disease such as cancer and inflammation. Many of the recently identified targets fall into the broad category of protein–protein interactions, which are simply not addressed by compounds with MW below 500. One superficial interpretation is that the key binding interactions – the so-called ‘hot spots’ – are widely dispersed over a large protein surface, and traditional small molecules have insufficient reach to derive adequate binding enthalpy.

A solution to this challenge is to discover and develop larger molecules, and drug launches during the last ten years have increasingly reflected the advent of biologic drugs – monoclonal antibodies or soluble receptors that can disrupt protein–protein interactions and provide unprecedented therapeutic efficacy. However, these drugs are administered parentally, as not unsurprisingly, they have zero oral bioavailability. Furthermore, most cannot penetrate cell membranes, and intracellular protein–protein complexes remain compelling but daunting targets for therapeutic intervention.

Cue the middle space molecules. Many researchers, both academic and industrial, now focus on the region of chemical space that exists between small molecules and biologics, based on the expectation that larger molecules (with MW between 500 and 1500) will more readily provide high affinity interactions with featureless protein surfaces, and yet can be optimised to achieve oral absorption and cell permeability.

Middle space molecules represent an assortment of different structural classes including peptides, peptidomimetics, macrocycles and natural products.^2–4 Indeed it is this final category that presents the strongest precedent for the pharmacology of this class. Natural products have evolved to fulfil numerous biochemical functions without any constraint on molecular weight. Whatever their intended activity in the parent organisms, many examples have exceptional pharmacological properties – affinity and selectivity for disease-relevant mammalian proteins – in addition to advantageous pharmacokinetic properties. Numerous antibiotics such as cyclosporine, vancomycin and erythromycin, and immunosuppressants such as rapamycin and FK-506 are middle space molecules with potent pharmacological activity and oral bioavailability.

The challenge for middle space research is to design similarly active compounds but in novel synthetically accessible forms, and to fine-tune physical properties so that irrespective of molecular weight, the compounds are orally bioavailable and can penetrate cell membranes. With this class of molecule, for the first time it is believed that important new target classes including intracellular protein–protein interactions will become increasingly tractable. This themed issue of MedChemComm, guest-edited by David Rees (Astex Pharmaceuticals) and myself, brings together papers from groups at the forefront of research into middle space molecules. There is a rapidly growing interest in this area of drug discovery, and we hope that readers will enjoy and be inspired by these articles.

References

1. C. A. Lipinski, F. Lombardo, B. W. Dominy and P. J. Feeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Delivery Rev., 1997, 23(1–3), 3–25.
2. E. M. Driggers, S. P. Hale, J. Lee and N. K. Terrett, The exploration of macrocycles for drug discovery – an underexploited structural class, Nat. Rev. Drug Discovery, 2008, 7(7), 608–624.
3. E. Marsault and M. L. Peterson, Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery, J. Med. Chem., 2011, 54(7), 1961–2004.
4. A. Ganesan, The impact of natural products upon modern drug discovery, Curr. Opin. Chem. Biol., 2008, 12(3), 306–317.

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