Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery
Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery
Efficient drug discovery is based on a concerted effort in optimizing bioactivity and compound properties such as lipophilicity, and is guided by efficiency metrics that reflect both aspects. While conformation-activity relationships and ligand conformational control are known strategies to improve bioactivity, the use of conformerspecific lipophilicities (logp) is much less explored. Here we show how conformer-specific logp values can be obtained from knowledge of the macroscopic logP value, and of the equilibrium constants between the individual species in water and in octanol. This is illustrated with fluorinated amide rotamers, with integration of rotamer 19F NMR signals as a facile, direct method to obtain logp values. The difference between logp and logP optimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery.
Linclau, Bruno
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Wang, Zhong
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Jefferies, Benjamin
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Graton, Jerome
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Le Questel, Jean-Yves
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Carbajo San Martin, Jesus
5e9093c8-1980-4e01-a2e1-ba0f9e53d2b9
Scott, James S.
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Sinnaeve, Davy
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7 February 2022
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Wang, Zhong
fe914552-33f1-4f0a-b8a1-52b82e8cb89e
Jefferies, Benjamin
09ae24cd-c590-4843-a548-c3b7bfe148bb
Graton, Jerome
a9189e35-d606-4adb-85b2-ad337a826dfb
Le Questel, Jean-Yves
38aea4ae-64a3-43b7-8049-ea2f351459f2
Carbajo San Martin, Jesus
5e9093c8-1980-4e01-a2e1-ba0f9e53d2b9
Scott, James S.
0fff1208-5c96-4490-8898-b9cc0692c8f3
Sinnaeve, Davy
1bff7c9e-d706-4318-9042-b291807752d6
Linclau, Bruno, Wang, Zhong, Jefferies, Benjamin, Graton, Jerome, Le Questel, Jean-Yves, Carbajo San Martin, Jesus, Scott, James S. and Sinnaeve, Davy
(2022)
Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery.
Angewandte Chemie, 61 (7), [e202114862].
(doi:10.1002/anie.202114862).
Abstract
Efficient drug discovery is based on a concerted effort in optimizing bioactivity and compound properties such as lipophilicity, and is guided by efficiency metrics that reflect both aspects. While conformation-activity relationships and ligand conformational control are known strategies to improve bioactivity, the use of conformerspecific lipophilicities (logp) is much less explored. Here we show how conformer-specific logp values can be obtained from knowledge of the macroscopic logP value, and of the equilibrium constants between the individual species in water and in octanol. This is illustrated with fluorinated amide rotamers, with integration of rotamer 19F NMR signals as a facile, direct method to obtain logp values. The difference between logp and logP optimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery.
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Accepted/In Press date: 14 December 2021
e-pub ahead of print date: 29 December 2021
Published date: 7 February 2022
Additional Information:
Funding Information:
We are grateful to AstraZeneca for a CASE award, and to the EPSRC for a CASE Conversion, a standard, and a core capability grant (EP/M508147/1, EP/M50662X/1, EP/P019943/1, EP/K039466/1). B.L. acknowledges the Research Foundation Flanders (FWO, Belgium) for an Odysseus Type I grant (G0F5621N). Prof. Marcel Utz (University of Southampton) is thanked for insightful discussions. Dr. Neil Wells is thanked for NMR spectroscopic support. Gert‐Jan Hofman and Tom Clough are thanked for providing the fluorinated prolines, and Emile Ottoy for the fluoroproline DFT calculations. Apollo Scientific is thanked for a gift of fluorinated piperidines and pyrrolidines.
Publisher Copyright:
© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
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Local EPrints ID: 453038
URI: http://eprints.soton.ac.uk/id/eprint/453038
ISSN: 0044-8249
PURE UUID: edd498de-f81e-4011-8e1c-58748064af50
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Date deposited: 07 Jan 2022 17:43
Last modified: 06 Jun 2024 01:38
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Contributors
Author:
Benjamin Jefferies
Author:
Jerome Graton
Author:
Jean-Yves Le Questel
Author:
Jesus Carbajo San Martin
Author:
James S. Scott
Author:
Davy Sinnaeve
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