A recent retrospective analysis of the conformational properties of lorlatinib suggest that a chameleonic conformational change may also play a role in its superior pharmaceutical properties. Peng et al. used molecular dynamics, validated by NMR, to show that in polar solvent (water/DMSO or pure water), the single conformer observed closely resembles the bound conformation seen crystallographically. However, in the non-polar solvent CHCl3, they additionally observed a second conformation in which the amide carbonyl is partly shielded by an aromatic group, contrasting with aqueous solution in which this polar group was fully exposed to solvent. Consequently, in the conformer that was observed only in CHCl3, the 3D polar surface area was somewhat lowered as was the dipole moment, increasing lipophilicity compared to the aqueous conformation. These results suggest that lorlatinib can adopt a less polar conformation when exposed to a nonpolar environment, potentially facilitating its entry into and passage through lipid membranes. It has been proposed that compounds with MW below 600-700 Da. do not necessarily require chameleonic conformational change for ordinary passive membrane permeability. Despite lorlatinib having a MW below this threshold, the chameleonic conformational adaptivity of this macrocycle may nonetheless contribute to the compound's permeability, and perhaps to the more stringent requirements for passing through the BBB.