Relating Conformational Equilibria to Conformer‐Specific Lipophilicities: New Opportunities in Drug Discovery

Bruno Linclau (1, 2) , Zhong Wang (1) , Benjamin Jeffries (1) , Jérôme Graton (3) , Rodrigo Carbajo (4) , Davy Sinnaeve (5, 6) , Jean‐yves Le Questel (3) , James Scott (4) , Elisabetta Chiarparin (4)

1 School of Chemistry [Southampton, UK]
2 Department of Organic and Macromolecular Chemistry
3 CEISAM - Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation
4 AstraZeneca [Cambridge, UK]
5 ERL 9002 - BSI - Biologie Structurale Intégrative
6 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167

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 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.

Mots clés: Amides; Conformation; Drug Development; Lipophilicity; NMR Spectroscopy

Domaines: Chimie thérapeutique; Chimie organique; Chimie théorique et/ou physique

Bruno Linclau, Zhong Wang, Benjamin Jeffries, Jérôme Graton, Rodrigo Carbajo, et al.. Relating Conformational Equilibria to Conformer‐Specific Lipophilicities: New Opportunities in Drug Discovery. Angewandte Chemie International Edition, 2022, 61 (7), pp.e202114862. ⟨10.1002/anie.202114862⟩. ⟨hal-03635530⟩