Revealing Atropisomer Axial Chirality in Drug Discovery

Abstract

An often overlooked source of chirality is atropisomerism, which results from slow rotation along a bond axis due to steric hindrance and/or electronic factors. If undetected or not managed properly, this time-dependent chirality has the potential to lead to serious consequences, because atropisomers can be present as distinct enantiomers or diastereoisomers with their attendant different properties. Herein we introduce a strategy to reveal and classify compounds that have atropisomeric chirality. Energy barriers to axial rotation were calculated using quantum mechanics, from which predicted high barriers could be experimentally validated. A calculated rotational energy barrier of 20 kcal mol(-1) was established as a suitable threshold to distinguish between atropisomers and non-atropisomers with a prediction accuracy of 86%. This methodology was applied to subsets of drug databases in the course of which atropisomeric drugs were identified. In addition, some drugs were exposed that were not yet known to have this chiral attribute. The most valuable utility of this tool will be to predict atropisomerism along the drug discovery pathway. When used in concert with our compound classification scheme, decisions can be made during early discovery stages such as "hit-to-lead" and "lead optimization," to foresee and validate the presence of atropisomers and to exercise options of removing, further stabilizing, or rendering the chiral axis of interest more freely rotatable via SAR design, thereby decreasing this potential liability within a compound series. The strategy can also improve drug development plans, such as determining whether a drug or series should be developed as a racemic mixture or as an isolated single compound. Moreover, the work described herein can be extended to other chemical fields that require the assessment of potential chiral axes.

Monte Carlo Simulations on Atropisomerism of Thienotriazolodiazepines Applicable to Slow Transition Phenomena Using Potential Energy Surfaces by <i>ab initio</i> Molecular Orbital Calculations

“…To evaluate the energy barriers around one acyclic rotational bond, LaPlante et al applied a molecular orbital (MO) method and obtained satisfactory results. 4) In addition to an atropisomerism caused by the rotational barrier of an acyclic bond, another kind of atropisomerism exists in the case of compounds with a medium-sized flexible ring. For such compounds, flexibility of the ring (ring inversion) causes atropisomers.…”

“…In addition to classical stereoisomers with chiral centers, much attention has been paid recently to the atropisomer. [2][3][4] A compound which has axial chiralities caused by hindered rotations about rotatable bonds shows atropisomerism. Compounds showing atropisomerism have long-lived (1000 s or longer) conformers that can be isolated, 5) and, like classical stereoisomers, each long-lived conformer often shows different biological activities.…”

“…Half lives (t 1/2 ) of the atropisomers are dependent on the energy barriers, thus the degree of atropisomerism is time-dependent. [2][3][4][5] For compounds with an energy barrier of 120 kJ/mol or higher, the atropisomers have a t 1/2 of several years at room temperature and behave like classical stereoisomers, but when the energy barrier is lower than 80 kJ/mol, the t 1/2 is less than 10 s and compounds behave as mixtures or are simply flexible compounds. Compounds with a moderate energy barrier of ca.…”

Principles, Concepts and Strategies of Stereoselective Synthesis

“…Enantiomers that resulted from highly hindered rotation about the single bonds and/or electronic factors are known as atropisomers. 19,20 A steric strain barrier to rotation in atropisomers is high enough to allow them to be isolated. In other words, atropisomers are stereoisomers where the element of chirality is not located on an atom but instead on a molecular plane or axis.…”

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.…”