Analysis of the Applicability and Use of Lipinski's Rule for Central Nervous System Drugs

Lipinski's Rule for central nervous system drugs (RoCNS), reported in 1999, predicts that poor absorption or permeation is more likely when there are more than three hydrogen bond donors (HBD), seven hydrogen bond acceptors (HBA), molecular weight (MW) is greater than 400 Da and CLog P is greater than five. The objective of this work was to evaluate the applicability of RoCNS for drugs approved from 1985 to 2014. Calculated physicochemical properties of central nervous system (CNS) drugs were compared to parameters established by the rule. From 1985 to 1999, 48 drugs were introduced for clinical therapy and 31% unsuited the RoCNS (among which six drugs did not fit within the determined CLog P, four the MW, four the HDA and two the HBD). From 2000 to 2014, 38 drugs were introduced and 32% violated RoCNS parameters (among which eight drugs did not fit within the determined MW, four the HBD, two the HBA and one the CLog P). These findings suggest that even though drugs introduced to the market after RoCNS publication showed a tendency to apply the rule, the application of the rule is similar for both periods. Examining the applicability of the RoCNS, it may serve as a guide for medicinal chemists designing future CNS-active small molecules.