Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery.
Amides
Conformation
Drug Development
Lipophilicity
NMR Spectroscopy
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
07 02 2022
07 02 2022
Historique:
received:
02
11
2021
pubmed:
17
12
2021
medline:
22
2
2022
entrez:
16
12
2021
Statut:
ppublish
Résumé
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 conformer-specific 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
Identifiants
pubmed: 34913249
doi: 10.1002/anie.202114862
pmc: PMC9304282
doi:
Substances chimiques
Octanols
0
Pharmaceutical Preparations
0
Water
059QF0KO0R
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202114862Subventions
Organisme : Fonds Wetenschappelijk Onderzoek
ID : G0F5621N
Organisme : Engineering and Physical Sciences Research Council
ID : EP/M508147/1
Organisme : Engineering and Physical Sciences Research Council
ID : EP/M50662X/1
Organisme : Engineering and Physical Sciences Research Council
ID : EP/P019943/1
Organisme : Engineering and Physical Sciences Research Council
ID : EP/K039466/1
Organisme : AstraZeneca UK
Informations de copyright
© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
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