Paradoxical Increase of Permeability and Lipophilicity with the Increasing Topological Polar Surface Area within a Series of PRMT5 Inhibitors

An
imidazolone → triazolone replacement addressed the limited
passive permeability of a series of protein arginine methyl transferase
5 (PRMT5) inhibitors. This increase in passive permeability was unexpected
given the increase in the hydrogen bond acceptor (HBA) count and topological
polar surface area (TPSA), two descriptors that are typically inversely
correlated with permeability. Quantum mechanics (QM) calculations
revealed that this unusual effect was due to an electronically driven
disconnect between TPSA and 3D-PSA, which manifests in a reduction
in overall HBA strength as indicated by the HBA moment descriptor
from COSMO-RS (conductor-like screening model for real solvation).
HBA moment was subsequently deployed as a design parameter leading
to the discovery of inhibitors with not only improved passive permeability
but also reduced P-glycoprotein (P-gp) transport. Our case study suggests
that hidden polarity as quantified by TPSA-3DPSA can be rationally
designed through QM calculations.