Topological polar surface area

A 2-dimensional estimate of the compound’s polar surface area (PSA) using the method proposed by Ertl et al. (Ertl et al. J. Med. Chem. (2000) 43 pp. 3714-3717). In this case, the model is based only on contributions from Nitrogen and Oxygen atoms has been used for consistency with other platforms; however, a more general model including Sulphur and Phosphorous has also been proposed.

A low PSA (PSA < 75 Å2)has been associated with an increased risk of adverse events due to non-specific toxicity, particularly when combined with high lipophilicity (log P > 4) (Hughes et al. Bioorg. Med. Chem. Lett. (2008) 18 pp. 4872-4875).

A high PSA has been associated with poor membrane permeability and, in particular, with low blood-brain-barrier penetration. For good oral bioavailability, an upper limit of 140 Å2 has been suggested, particularly when associated with a large number of rotatable bonds (≥10) (Veber et al. J. Med. Chem. (2002) 45 pp. 2615-2623). For blood-brain barrier presentation, a stricter criterion of PSA < 80 Å2 has been proposed (Chico et al. Nat. Rev. Drug Discov. (2009) 8 pp. 892-909).