The Challenge of Atropisomerism in Drug Discovery

Abstract

A twist in the tale: Recent reports have highlighted solutions to the problems encountered when drug candidates exist as slowly interconverting conformers or atropisomers (see scheme). This Minireview brings together the various strategies that have been adopted and proposes a general approach to handling an aspect of stereochemistry which has received little attention from drug regulatory agencies.

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.…”

Heavily Substituted Atropisomeric Diarylamines by Unactivated Smiles Rearrangement of N‐Aryl Anthranilamides

“…[3] Although the stereochemistry of most atropisomers derives from slow rotation about a C-C single bond, C-O, [4] C-S [5] and C-N atropisomers are also known, [6] and they too show great promise as new families of ligands or as medicinally active compounds. The diarylamine motif is a privileged pharmacophore, present in major drugs such as the analgesic diclofenac and the diuretic torasemide.…”

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

“…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.…”

“…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. 2,3) Atropisomerism is caused by the high energy barrier between long-lived conformers due to the steric and/or electronic repulsions and is often observed in compounds with bulky substituents in the ortho positions. Half lives (t 1/2 ) of the atropisomers are dependent on the energy barriers, thus the degree of atropisomerism is time-dependent.…”

“…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.…”