Exploration of piperidine 3D fragment chemical space:synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates

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 report the synthesis of piperidine-based 3D fragment building blocks - 20 regio- and diastereoisomers of methyl substituted pipecolinates using simple and general synthetic methods. cis-Piperidines, accessed through a pyridine hydrogenation were transformed into their trans-diastereoisomers using conformational control and unified reaction conditions. Additionally, diastereoselective lithiation/trapping was utilised to access trans-piperidines. Analysis of a virtual library of fragments derived from the 20 cis- and trans-disubstituted piperidines showed that it consisted of 3D molecules with suitable molecular properties to be used in fragment-based drug discovery programs.

Metadata

Item Type:	Article
Authors/Creators:	Jones, S. Paul Firth, James D. (jdf511@york.ac.uk) Wheldon, Mary C. Atobe, Masakazu Hubbard, Roderick E. https://orcid.org/0000-0002-8233-7461 Blakemore, David C. De Fusco, Claudia Lucas, Simon C.C. Roughley, Stephen D. Vidler, Lewis R. Whatton, Maria Ann Woolford, Alison J.A. Wrigley, Gail L. O'Brien, Peter https://orcid.org/0000-0002-9966-1962
Copyright, Publisher and Additional Information:	Funding Information: We are grateful to AstraZeneca, Astex Pharmaceuticals, Lilly, Pfizer and Vernalis for supporting this venture. When this research was carried out, CDF was employed by AstraZeneca and LRV and MAW were employed by Lilly. MA is currently employed by Modulus Discovery. This project was funded by the EPSRC (MCW), BBSRC (BB/N008332/1) (JDF), University of York (SPJ), Asahi Kasei (MA) and The Royal Society (Industry Fellowship, INF\R1\191028) (POB). We thank Biovia for supplying Pipeline Pilot software. Publisher Copyright: © The Royal Society of Chemistry 2022
Dates:	Published: 1 December 2022 Published (online): 11 October 2022 Accepted: 26 September 2022
Institution:	The University of York
Academic Units:	The University of York > Faculty of Sciences (York) > Chemistry (York)
Depositing User:	Pure (York)
Date Deposited:	19 Dec 2022 14:10
Last Modified:	01 Dec 2024 01:21
Published Version:	https://doi.org/10.1039/d2md00239f
Status:	Published
Refereed:	Yes
Identification Number:	10.1039/d2md00239f
Related URLs:	http://www.scopus.com/inward/record.url?...
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:194592

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Exploration of piperidine 3D fragment chemical space:synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates

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