Relating Conformational Equilibria to Conformer‐Specific Lipophilicities: New Opportunities in Drug Discovery. (29th December 2021)

• Record Type: Journal Article
• Authors: Linclau, Bruno; Wang, Zhong; Jeffries, Benjamin; Graton, Jérôme; Carbajo, Rodrigo J.; Sinnaeve, Davy; Le Questel, Jean‐Yves; Scott, James S.; Chiarparin, Elisabetta
• Is Part Of: Angewandte Chemie. Volume 134:Number 7(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-29
• Subjects: Amides -- Conformation -- Drug Development -- Lipophilicity -- NMR Spectroscopy; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202114862
• Languages: English
• ISSNs: 0044-8249

Abstract

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 conformer‐specific lipophilicities (log p ) is much less explored. Here we show how conformer‐specific log p values can be obtained from knowledge of the macroscopic log P 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 19 F NMR signals as a facile, direct method to obtain log p values. The difference between log p and log P optimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery. Abstract : Catching conformations: Lipophilicity (log P ) is a molecular property which is nevertheless the weighted average of the lipophilicities of the individual conformers. The first direct measurement of conformer‐specific lipophilicity values is presented, together with the introduction of a new avenue for rational lipophilicity optimization of drug candidates which is focused on modification of conformational equilibria in water and in octanol.