Assessing Atropisomer Axial Chirality in Drug Discovery and Development

Abstract

An underlying goal of drug discovery is to develop safe and stable substances that specifically target essential elements that cause disease. Molecular chirality adds an additional level of specificity and complexity in achieving this objective, as mirror image molecules are distinct substances and must be treated as such. Classical chiral-center enantiomers ( Figure 1A) have been shown to differ significantly in biological activity, pharmacodynamics, pharmacokinetics, and toxicity. 1 The cases of thalidomide 2 and perhexiline, 3 whose enantiomers differ dramatically with respect to toxicity and metabolic properties, emphasize the importance of addressing stereochemistry in drug development.In this Perspective, we address the pharmaceutical implications of a largely overlooked alternative source of drug chirality, atropisomerism, 4 which has the distinct feature of creating molecular chirality as a result of hindered rotation about a bond axis ( Figure 1B). Figure 1C shows space-filling models where it is evident that rotation about the vertical axis is hindered because of steric clashes between the bulky R1 and R2 groups with R3 and R4.Unlike compounds with classical chiral centers, which are often stable and which racemize via a bond breaking and making process, atropisomers racemize via an intramolecular dynamic process that only involves bond rotation. As bond rotation is time-dependent, racemization half-lives for atropisomers can vary dramatically between minutes to years, depending on the degree of steric hindrance, electronic influences, temperature, solvent, etc. Because of this time-dependent feature, drug discovery campaigns can become more complex, or may even be abandoned, when atropisomeric properties are observed. Atropisomerism frequently results as researchers strive to design more compact and conformationally constrained inhibitors. Even for courageous design and synthetic campaigns that attempt to develop atropisomeric compounds, important differences in properties have been reported for enantiomeric pairs, such as in vitro inhibition, crystallization, in vivo racemization rates, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. There are also examples of compounds that were unknowingly developed as a racemic mixture of atropisomers and required chiral detection experiments to finally reveal their existence. Overall, many view atropisomer chirality as a lurking menace with the potential to increase the cost of pharmaceutical research and development and to derail drug Figure 1. (A) Mirror-image enantiomers S and R arise from a classical chiral center (atom). (B) Other enantiomers S a and R a can arise from hindered rotation that creates a chiral axis. (C) Atropisomeric enantiomers S a and R a are shown as space-filling models. Reproduced with permission from ChemMedChem (LaPlante, S. R.; Edwards, P. J.; Fader, L. D.; Jakalian, A.; Hucke, O. Revealing atropisomer axial chirality in drug discovery. 2011, 6, 505À513,

Imidazopyridine-Based Fatty Acid Synthase Inhibitors That Show Anti-HCV Activity and in Vivo Target Modulation

“…Treatment of 2,4-dimethylbenzoic acid (25) iodine and sodium periodate in a mixture of sulfuric acid and acetic acid furnished the iodinated aryl compound 26 in 82% yield. Lithium-halogen exchange followed by addition of N,Ndimethylformamide (DMF) gave the corresponding aldehyde derivative (27) In the proton NMR spectrum of 19, the signal for the R 3 -methyl was split (Δδ ≈ 40 Hz, d 6 -DMSO), suggesting a possible hindered rotation around the phenyl-carbonyl bond. Preliminary estimates of rotational barriers in compound 19 were determined using VT-NMR.…”

Understanding Chemistry and Unique NMR Characters of Novel Amide and Ester Leflunomide Analogues

“…Both the geometry of the N-Ar bond and its rotation barrier are crucial features in areas as diverse as enzyme/substrate binding [9][10][11].…”

Discovery and Assessment of Atropisomers of (±)-Lesinurad

“…19,20 A recent review from LaPlante and co-workers proposed that atropisomers could be classified into three groups based on rotational energy barriers and racemization rates (t 1/2 ) (Class 1, rapid equilibration with t 1/2 less than minutes; Class 2, moderate rate of equilibration with t 1/2 from hours to days; Class 3, very slow equilibration with t 1/2 in years). 18,21 Since atropisomers in Class 3 are as stable as classical chiral compounds, they could be isolated and treated as single enantiomers.…”