Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes

ACS Chem Neurosci. 2010 Jun 16;1(6):420-34. doi: 10.1021/cn100007x. Epub 2010 Mar 25.


As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.

Keywords: CNS candidates; CNS drugs; Central nervous system (CNS); Madin−Darby canine kidney; P-glycoprotein; cellular toxicity; dofetilide binding; drug−drug interactions; high-throughput screening; human liver microsome stability; hydrogen bond donor; ligand efficiency; ligand-efficiency-dependent lipophilicity; ligand-lipophilicity efficiency; lipophilicity; molecular weight; most basic pKa; passive permeability; polarity; topological polar surface area; transformed human liver epithelial cells; unbound intrinsic clearance.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Cell Line
  • Cell Survival / drug effects
  • Central Nervous System / drug effects*
  • Central Nervous System Agents / chemistry*
  • Central Nervous System Agents / metabolism
  • Central Nervous System Agents / pharmacology*
  • Dogs
  • Drug Design
  • Epithelial Cells / drug effects
  • Humans
  • Safety
  • Solubility


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Central Nervous System Agents