Affiliation: | 1. Department of Chemistry, University of York, Heslington, York, YO10 5DD UK;2. Medicine Design, Pfizer Inc, 445 Eastern Point Road, Groton, CT 06340 USA;3. Discovery Sciences, R&D, AstraZeneca, Cambridge, CB4 0WG UK;4. Vernalis (R&D) Ltd, Granta Park, Abington, Cambridge, CB21 6GB UK;5. Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH UK;6. Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA UK;7. Medicinal Chemistry, Oncology R&D, AstraZeneca, CB4 0WG Cambridge, UK |
Abstract: | Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol−1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity. |