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Reducing the lipophilicity of perfluoroalkyl groups by CF2–F/CF2-Me or CF3/CH3 exchange’

Reducing the lipophilicity of perfluoroalkyl groups by CF2–F/CF2-Me or CF3/CH3 exchange’
Reducing the lipophilicity of perfluoroalkyl groups by CF2–F/CF2-Me or CF3/CH3 exchange’
Fluorination is commonly employed to optimize bioactivity and pharmaco-kinetic properties of drug candidates. Aliphatic fluorination often reduces the lipophilicity (log P), but polyfluoroalkylation typically increases lipophilicity. Hence, identification of polyfluorinated motifs that nonetheless lead to similar or even reduced lipophilicities is of interest to expand the arsenal of medicinal chemistry tools in tackling properties such as compound metabolic stability or off-target selectivity. We show that changing a CF3-group of a perfluoroalkyl chain to a methyl group leads to a drastic reduction in lipophilicity. We also show that changing a C–F bond of a trifluoromethyl group, including when incorporated as part of a perfluoroalkyl group, to a C–Me group, leads to a reduction in log P, despite the resulting chain elongation. The observed lipophilicity trends were identified in fluorinated alkanol models and reproduced when incorporated in analogues of a drug candidate, and the metabolic stability of these motifs was demonstrated.
0022-2623
10602-10618
Jeffries, Benjamin
09ae24cd-c590-4843-a548-c3b7bfe148bb
Wang, Zhong
fe914552-33f1-4f0a-b8a1-52b82e8cb89e
Graton, Jérôme
12432694-552e-4a40-9935-9ff7c77fbf07
Holland, Simon
e0afa720-08a1-4519-85d6-d508a96e29df
Brind, Thomasin
ba917f11-4122-404b-939c-a5f06cc84038
Greenwood, Ryan D.R.
ef4c47c6-d38d-49a5-9edb-51fe404c27f5
Le Questel, Jean-Yves
38aea4ae-64a3-43b7-8049-ea2f351459f2
Scott, James S.
0fff1208-5c96-4490-8898-b9cc0692c8f3
Chiarparin, Elisabetta
5051f89a-b801-4746-8f20-457fdcbed396
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Jeffries, Benjamin
09ae24cd-c590-4843-a548-c3b7bfe148bb
Wang, Zhong
fe914552-33f1-4f0a-b8a1-52b82e8cb89e
Graton, Jérôme
12432694-552e-4a40-9935-9ff7c77fbf07
Holland, Simon
e0afa720-08a1-4519-85d6-d508a96e29df
Brind, Thomasin
ba917f11-4122-404b-939c-a5f06cc84038
Greenwood, Ryan D.R.
ef4c47c6-d38d-49a5-9edb-51fe404c27f5
Le Questel, Jean-Yves
38aea4ae-64a3-43b7-8049-ea2f351459f2
Scott, James S.
0fff1208-5c96-4490-8898-b9cc0692c8f3
Chiarparin, Elisabetta
5051f89a-b801-4746-8f20-457fdcbed396
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba

Jeffries, Benjamin, Wang, Zhong, Graton, Jérôme, Holland, Simon, Brind, Thomasin, Greenwood, Ryan D.R., Le Questel, Jean-Yves, Scott, James S., Chiarparin, Elisabetta and Linclau, Bruno (2018) Reducing the lipophilicity of perfluoroalkyl groups by CF2–F/CF2-Me or CF3/CH3 exchange’. Journal of Medicinal Chemistry, 61 (23), 10602-10618. (doi:10.1021/acs.jmedchem.8b01222).

Record type: Article

Abstract

Fluorination is commonly employed to optimize bioactivity and pharmaco-kinetic properties of drug candidates. Aliphatic fluorination often reduces the lipophilicity (log P), but polyfluoroalkylation typically increases lipophilicity. Hence, identification of polyfluorinated motifs that nonetheless lead to similar or even reduced lipophilicities is of interest to expand the arsenal of medicinal chemistry tools in tackling properties such as compound metabolic stability or off-target selectivity. We show that changing a CF3-group of a perfluoroalkyl chain to a methyl group leads to a drastic reduction in lipophilicity. We also show that changing a C–F bond of a trifluoromethyl group, including when incorporated as part of a perfluoroalkyl group, to a C–Me group, leads to a reduction in log P, despite the resulting chain elongation. The observed lipophilicity trends were identified in fluorinated alkanol models and reproduced when incorporated in analogues of a drug candidate, and the metabolic stability of these motifs was demonstrated.

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Linclau manuscript_corr BLv4 - Accepted Manuscript
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Accepted/In Press date: 31 October 2018
e-pub ahead of print date: 9 November 2018
Published date: 13 December 2018

Identifiers

Local EPrints ID: 426422
URI: http://eprints.soton.ac.uk/id/eprint/426422
ISSN: 0022-2623
PURE UUID: f732d25b-1544-43d1-b932-ec66a43c0174
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170

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Date deposited: 27 Nov 2018 17:30
Last modified: 15 Sep 2021 05:09

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Contributors

Author: Benjamin Jeffries
Author: Zhong Wang
Author: Jérôme Graton
Author: Simon Holland
Author: Thomasin Brind
Author: Ryan D.R. Greenwood
Author: Jean-Yves Le Questel
Author: James S. Scott
Author: Elisabetta Chiarparin
Author: Bruno Linclau ORCID iD

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