Moebitz, Henrik (2023) Design principles for balanced lipophilicity and permeability in beyond Rule of 5 space. ChemMedChem : chemistry enabling drug discovery. ISSN 1860-71791860-7187

Abstract

A conformational analysis of all oral bRo5 drugs using a QM-based workflow and experimental structures revealed similar polar surface area (PSA) thresholds as for Ro5 drugs and a modest impact of environments on 3D-PSA and intramolecular hydrogen bond (IMHB) count (often termed chameleonicity) despite a significant difference between TPSA and 3D PSA. The minimum TPSA-3D PSA to maintain permeability in bRo5 space depends on the fraction of polarity (TPSA/MW). TPSA/MW in the bRo5 and Ro5 oral drugs sets had a median of ~0.2 Å2/Da, with the upper half corresponding to the upper decile of logP < 5 in the Novartis logP set. TPSA/MW distributions of Novartis compounds with balanced lipophilicity and permeability narrowed with increasing MW to a range between 0.12-0.3. The range of 0.2-0.3 Å2/Da and PSA > 100 Å2 de-fines the sweet spot of this "rule of 1/5" occupied by the majority of oral bRo5 drugs. TPSA-3DPSA increased in the lead optimization (LO) campaigns of three first in class de novo designed bRo5 drugs and may be a useful parameter for future bRo5 LO campaigns.

Item Type:	Article
Keywords:	oral bRo5 drugs, chameleonicity. conformation, permeability, logP, quantum chemistry, ReSCoSS, COSMO-RS
Date Deposited:	16 Dec 2023 00:45
Last Modified:	16 Dec 2023 00:45
URI:	https://oak.novartis.com/id/eprint/48163