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

TY - JOUR

T1 - Exploration of piperidine 3D fragment chemical space

T2 - synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates

AU - Jones, S. Paul

AU - Firth, James D.

AU - Wheldon, Mary C.

AU - Atobe, Masakazu

AU - Hubbard, Roderick E.

AU - Blakemore, David C.

AU - De Fusco, Claudia

AU - Lucas, Simon C.C.

AU - Roughley, Stephen D.

AU - Vidler, Lewis R.

AU - Whatton, Maria Ann

AU - Woolford, Alison J.A.

AU - Wrigley, Gail L.

AU - O'Brien, Peter

N1 - 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

PY - 2022/12/1

Y1 - 2022/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85141874002&partnerID=8YFLogxK

U2 - 10.1039/d2md00239f

DO - 10.1039/d2md00239f

M3 - Article

AN - SCOPUS:85141874002

SN - 2632-8682

VL - 13

SP - 1614

EP - 1620

JO - RSC Medicinal Chemistry

JF - RSC Medicinal Chemistry

IS - 12

ER -