Design Principles for Balancing Lipophilicity and Permeability in beyond Rule of 5 Space

An ab initio conformational analysis of oral beyond Rule of 5 (bRo5) drugs was complemented with measured permeability and logP(octanol) to derive design principles conferring oral bioavailability. 3D polar surface area (PSA) thresholds for oral bRo5 drugs coincided with those reported for Ro5 space. The majority of oral bRo5 drugs exceeded the Ro5 logP threshold of 5, reflecting a bias for permeability. Above 500 Da molecular weight (MW), oral drugs and highly permeable Novartis compounds occupy a narrow polarity range (topological or TPSA/MW) of 0.1-0.3 Å