Title:Analysis of the Applicability and Use of Lipinski`s Rule for Central Nervous System Drugs
VOLUME: 13 ISSUE: 10
Author(s):Thais B. Fernandes, Mariana C. F. Segretti, Michelle C. Polli and Roberto Parise-Filho
Affiliation:Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, 580 Lineu Prestes Av, São Paulo, Brazil.
Keywords:Drug design, central nervous system, oral absorption, bioavailable, Lipinski's rule.
Abstract: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.
