Reflecting on 30 Years as a Medicinal Chemist

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A blog from Principal Research Chemist, Phil Thorne.

1st Aug 2022 brings around 30 years of experience as a synthetic organic medicinal chemist in the pharmaceutical industry – a job I still love, as my colleagues can attest. To mark this milestone, I am sharing some personal observations / recollections / reflections on how the job has changed in that time!

Route planning has moved from corporate knowledge and card indexes of interesting transformations; to software Scifinder and Reaxys. Indeed, today a computer per chemist, rather than a terminal to a VAX mainframe.

Compound novelty determination is no longer knowing the CAS name of your molecule and searching the whole Chem Abs Collective indexes.

Calculating physical properties ahead of synthesis and not prosecuting those that fall out of desired chemical space.

Serendipity in finding new reactions / keeping abreast of current literature has evolved from thumbing through hard copy journal issues, in the library (away from distractions); to finding time to browse electronic issues on a computer.

The wet work is still carried out in round bottom flasks, on stirrer hotplates, in the main – with heat transferred with metal blocks rather than oil baths. We do now have flow chemistry, photochemistry and electrochemistry becoming mainstream. Combinatorial chemistry arrived; borrowing 96 well plate technology, liquid handlers and micro pipettes from biosciences; as multiple compounds per well unpurified and evolved to 1 compound per well, purified & characterised by LCMS/NMR. Palladium chemistry, first reported in the literature in the late 1970s, is now mainstream, rather than new / specialised transformation.

Purification has moved on from loose silica columns to prepacked cartridges for both normal and reverse phase. There is also now SFC chromatography. When I started, HPLC to the bench chemist was normal phase: 2 Waters 510 pumps and a chart recorder. Trituration, recrystallization and acid / base cycles still form an important part of the repertoire of purification techniques.

Having made and purified a new compound, confirming identity is fundamental. The main stays are still a mass spectrum and NMR. Back then a single injection into the vacuum of a FAB mass spectrometer, an instrument that took up a whole room and needed a specialist operator. NMR was a 250MHz magnet and manual shim each sample. Today we have automated UPLC-MS and NMR, with at least 400MHz magnet. Techniques that have faded away from routine: UV (still can get from UPLC), IR, elemental analysis. Software to process NMR spectra, supplying interpretation with multiplicity and J values all calculated.

Recording of wet work was in handwritten hard bound lab books (I have had many comments on my handwriting readability!); today we have electronic repository in ELN, which is fully searchable.

Quantities to be made: 250mg of final compound after characterisation, plus 250mg of every intermediate for the company file (screening collection). Primary assays have come down in their requirements from 10s of mg to 1mg, as a stock 10mM DMSO solution, covering a whole wave of assays.

Initial project screening has moved on from chasing potency only. Now in wave 1 screening there is a holistic approach: primary assay, selectivity assay, chrom logP/D, Clint in heps and mics, cyp panel, solubility.

Determining structure activity relationships (SAR) from generated data, has moved on from excel spreadsheets to customized software.

The one piece of the drug discovery puzzle I am still missing is getting a molecule to market, that is how tough the job is. Best shot to date was AZD9056, making it to Clinical Phase IIb.

Continued professional development is still highly important and integral to the work, be that sharing knowledge between colleagues (mentoring), in-house courses, external courses or conference attendance (domestic and international); both in synthetic chemistry and medicinal chemistry disciplines. A constant requirement throughout has been to report back to colleagues on learnings in some form – written or oral.