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

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 (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 19 F 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.

Effect of gem‐Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes

“…A recent elegant study Chemistry-A European Journal dealing with mono-and difluorinated pyrrolidine / piperidine derivatives showed that conformational equilibria can lead to experimentally measurable effects on the LogP values. [53] Interestingly, a different order of lipophilicity was observed for acyclic derivatives 3.0β-δ and 4.0β-δ: δ < γ < β. In other words, while acyclic δ and γ isomers demonstrated behavior like that of cycloalkanes, acyclic β isomers had considerably…”

“…For a more detailed discussion of these observations, a thorough conformational analysis of amides 3 and 4 in aqueous and organic media is required, which is to be performed in the upcoming work. A recent elegant study dealing with mono‐ and difluorinated pyrrolidine / piperidine derivatives showed that conformational equilibria can lead to experimentally measurable effects on the Log P values [53] …”

Impact of Fluoroalkyl Substituents on the Physicochemical Properties of Saturated Heterocyclic Amines

“…Conformation-specific lipophilicities of fluorinecontaining piperidines and pyrrolidines were recently discussed in the literature. [19]…”

“…A number of insightful studies that summarize the impact of various fluorination patterns on the compound's physicochemical and pharmacokinetic parameters started to emerge over the last decade. [15][16][17][18][19] In one of their contributions, Müller and co-authors suggested that the dipole moment of the vicdifluoro moiety is 1.4 times higher than that of the gem-difluoro moiety based on a simple vector analysis approach. [20] Later on, this assumption was experimentally confirmed by showing a lipophilicity decrease in vic-difluoro-substituted derivatives A1 and A2, and a basicity decrease in A1 compared to their gemdifluoro-substituted counterparts (Figure 1A).…”

Palladium-catalyzed enantioselective (2-naphthyl)methylation of azaarylmethyl amines

“…Nitrogen containing aromatic compounds are widespread in small-molecule drugs, pharmaceuticals, agrochemicals and natural products. [1][2][3][4][5][6] Among nitrogen containing compounds, azaarylmethyl amines frequently exhibit bioactivity, including antitumor, 7 antihistamine 8 and anti-HIV properties. 9 The preparation of enantioenriched α-azaarylmethyl amines has been inspired, in part, by a drive from the pharmaceutical industry to increase the number of amino groups in molecules to be tested for bioactivity.…”