title: Novel tactics for designing water-soluble molecules in drug discovery.
abstract: BACKGROUND
  Physiochemical drug properties, such as aqueous solubility are considered to be a major factor in determining the ultimate success or failure of experimental agents. Solubility is important because it determines the maximum dose which can be taken up. As the size and hydrophobicity of drug candidates has increased over the years, poor solubility has become a more prevalent issue. Recent examples from the literature show that an improved understanding of the relationship between molecular structure and solubility allows this issue to be approached using rational design.
  
  
  METHODS
  This review provides selected examples from the recent drug discovery literature that demonstrate various tactics, which have been applied successfully towards improving drug solubility. The examples that were selected demonstrate the underlying principles behind aqueous solubility, such as hydrophobicity and crystalline stability.
  
  
  CONCLUSIONS
  From a strategic point of view, improving the solubility of a compound should be straightforward because it can be accomplished by simply reducing hydrophobicity or crystalline stability. However, the structural elements and physical properties which control solubility also influence potency, pharmacokinetics and toxicity. Furthermore, there are practical aspects such as the quantity and quality of solubility-related data, which hamper the development of structure-solubility relationships. Given that poor aqueous solubility remains a primary issue in drug discovery, there is a continuous need for novel methods to overcome it.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research and Development, Department of Medicinal Chemistry , 5 Research Parkway, Wallingford, CT 06492 , USA +1 203 677 6686 ; michael.a.walker@bms.com.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Walker
mesh_terms: D000465:Algorithms; D055808:Drug Discovery; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D014867:Water
keywords: aqueous solubility; crystal packing; crystalline stability; drug properties; general solubility equation; hydration; hydrophobicity; melting point; solvation