NMR in Pharmaceutical Science

Jeremy R. Everett, Robin K. Harris, John C. Lindon, Ian D. Wilson, Jeremy R. Everett, Robin K. Harris, John C. Lindon, Ian D. Wilson

• Publisher: Wiley
• Year: 2015
• ISBN:
  9781118660232
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Spectroscopy & Spectrum Analysis

NMR in Pharmaceutical Sciences is intended to be a comprehensive source of information for the many individuals that utilize MR in studies of relevance to the pharmaceutical sector. The book is intended to educate and inform those who develop and apply MR approaches within the wider pharmaceutical environment, emphasizing the toolbox that is available to spectroscopists and radiologists.

This book is structured on the key processes in drug discovery, development and manufacture, but underpinned by an understanding of fundamental NMR principles and the unique contribution that NMR (including MRI) can provide. After an introductory chapter, which constitutes an overview, the content is organised into five sections. The first section is on the basics of NMR theory and relevant experimental methods. The rest follow a sequence based on the chronology of drug discovery and development, firstly 'Idea to Lead' then 'Lead to Drug Candidate', followed by 'Clinical Development', and finally 'Drug Manufacture'. The thirty one chapters cover a vast range of topics from analytical chemistry, including aspects involved in regulatory matters and in the prevention of fraud, to clinical imaging studies.

Whilst this comprehensive volume will be essential reading for many scientists based in pharmaceutical and related industries, it should also be of considerable value to a much wider range of academic scientists whose research is related to the various aspects of pharmaceutical R&D; for them it will supply vital understanding of pharmaceutical industrial concerns and the basis of key decision making processes.

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Part D
Lead to Drug Candidate

Chapter 14
NMR-based Structure Determination of Drug Leads and Candidates

Torren M. Peakman

[email protected]

1. 14.1 Introduction
2. 14.2 Background to Structure Determination by NMR in the Pharmaceutical Industry
3. 14.3 Information from NMR Experiments for Structure Determination
4. 14.4 Constitution. Use of C NMR Chemical Shift Predictions and H–C Chemical Shift Correlations from HSQC and HMBC Spectra
5. 14.5 Stereochemistry Problems. Proton–Proton Through-space Correlations
6. 14.6 Use of the N Isotope
7. 14.7 Examples Where H NMR Spectra are Broad or Contain More than One Species in Solution
8. 14.8 Conclusions
9. References

14.1 Introduction

Two recent articles in Chemical & Engineering News^{1, 2} clearly highlight the importance of correct structure assignment in the pharmaceutical industry. In this case, the structure of a patented anticancer compound known as TIC10 or ONC201 (1), that is about to enter human clinical trials, has been reassigned as the ‘angular’ isomer (2).³ The implications of this error are considerable^{1, 2} and there is little doubt that a large number of medicinal chemists have shaken their heads in disbelief at this revelation. Indeed, one posting (Corante Weblogs. In the Pipeline: drug discovery. http://pipeline.corante.com/archives/2014/05/22/a_horrible_expensive_and_completely_avoidable_drug_development_mixup.php) has described it as ‘a horrible, expensive, and completely avoidable drug development mix-up’.

Within the public domain, this error is far from a one off! The Pfizer anticancer compound bosutinib (3), currently undergoing Phase III clinical trials for chronic myeloid leukemia, has been marketed by a number of suppliers with some of these inadvertently selling the isomeric structure (4) containing a 3,5-dichloro-4-methoxyanilide rather than a 2,4-dichloro-5-methoxyanilide.⁴ This has unfortunately led to a large number of academic results being invalidated without mentioning the time and cost involved.⁴ An interesting discussion on how NMR spectroscopy could have been used to prevent this happening has appeared on Ryan's blog (Ryan's Blog on NMR Software. http://acdlabs.typepad.com/my_weblog/2012/06/the-bosutinib-isomer-a-case-for-nmr-asv.html).

These two striking examples highlight the importance of correct structure assignment of drug leads and candidates and many in the pharmaceutical industry have no doubt lost count of the number of wrong compounds, supplied or even synthesized in house, that they have come across.

Pharmaceutical companies possess large numbers of compounds in their compound collection, typically between tens and hundreds of thousands. It is probably fair to say that in many of these collections, the number of samples with the wrong structure to that documented is 10–20%. Indeed, this scenario occurred in the case of TIC10 with the compound being obtained from the National Cancer Database.^{1, 2} Over the past two decades, parallel chemistry has no doubt reduced the number of incorrect structures in compound collections. Following the merger of Glaxo Wellcome and SmithKline Beecham in 2000, the new company GlaxoSmithKline embarked on a review of their combined compound collection.⁵ Compounds were initially screened by liquid chromatography–mass spectrometry (LC-MS) with those being pure and having the correct mass to the documented structure being assumed to be correct, while those being pure but having the wrong mass being submitted for NMR structure determination.⁵ The reader will no doubt note that isomeric structures such as those highlighted earlier would have slipped through the net! This exercise, however, clearly shows how seriously companies such as GlaxoSmithKline take the issue of correct structural identity⁵ (see Chapter 11). Interestingly, there is now a trend emerging in the pharmaceutical industry towards reducing the number of compounds synthesized and thinking more deeply about why such a compound is being prepared in the first place. With this increased emphasis on design, the need for correct structure assignment is clearly ever more crucial. Although not an area covered in this chapter, NMR studies can be fruitful in determining some of the key physical properties of small drug-like molecules that can drive this understanding.

14.2 Background to Structure Determination by NMR in the Pharmaceutical Industry

So when should structure determination by NMR become a key tool in a drug discovery program? Let us assume that a screen against a particular target has been completed and a number of hits from the compound collection have resulted. A medicinal chemist will look at selecting the most interesting of these to progress further, with the ultimate aim of finding several distinct entities as starting points from which to launch synthetic chemistry campaigns to make molecules with improved drug-like properties. Returning to my comment that typically 10–20% of compounds in compound collections have the wrong structure to that documented, structure confirmation would clearly be worthwhile. Clearly, this was not the case with TIC10 with the structure being assumed to be that registered (1) and not the revised structure (2).^{1, 2} Medicinal chemists will want to resynthesize and retest the interesting hit compounds to confirm activity and to eliminate the chance of any contaminant in the original material triggering a false positive. It is worthwhile expanding on this point about being sure of the correct structure at the beginning. Starting with an incorrect structure could easily send a project down the wrong path. What about the scenario of a chemist starting with the wrong intermediate as no doubt occurred in the case of the intended commercial synthesis of bosutinib (3) that actually transpired to be the isomeric structure (4)? There has been a fair amount of discussion of when to acquire more data than just a ¹H NMR and an LC-MS. Some people have advocated doing this on final compounds. This is a fair point and certainly would give a lot of confidence to the project. If the extra data proved that the structure was wrong then there has been a significant waste of manpower and money in finding the error at the end point. Certainly, it is better to have found the error but finding the mistake earlier in the day would have been advantageous. Imagine the scenario where the starting material is wrong and a chemist spent a week or more taking it through to the final product only to find out that it possessed the wrong structure! To avoid just this situation occurring, companies such as Pfizer utilize online liquid chromatography–evaporative light scattering–mass spectrometry (LC-ELSD-MS) systems in order to conf...