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 molecules13109991006CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPnão temnão tem2013/18160-

Thiol-Based Potent and Selective HDAC6 Inhibitors Promote Tubulin Acetylation and T‑Regulatory Cell Suppressive Function

Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, <b>2b</b>, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1. <b>2b</b> also showed excellent efficacy at increasing tubulin acetylation in rat primary cortical cultures, inducing a 10-fold increase in acetylated tubulin at 1 μM. To assess possible therapeutic effects, compounds were assayed for their ability to increase T-regulatory (Treg) suppressive function. Some but not all of the compounds increased Treg function, and thereby decreased conventional T cell activation and proliferation <i>in vitro</i>