Investigating the effects of the core nitrogen atom configuration on the thermodynamic solubility of 6,​5-​bicyclic heterocycles

Brett Cosgrove, Kenneth Down, Sophie Bertrand, Nicholas C.O. Tomkinson, Michael D. Barker

Research output: Contribution to journalArticlepeer-review

Abstract

Physicochemical properties, such as solubility, are important when prioritising compounds for progression on a drug discovery project. There is limited literature around the systematic effects of core changes on thermodynamic solubility. This work details the synthesis of nitrogen containing 6,5-bicyclic heterocyclic cores which are common scaffolds in medicinal chemistry and the analysis of their physicochemical properties, particularly, thermodynamic solubility. Crystalline solids were obtained where possible to enable a robust comparison of the thermodynamic solubility. Other parameters such as pKa, melting point and lipophilicity were also measured to determine the key factors affecting the observed solubility.
Original languageEnglish
Article number127752
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume33
Early online date29 Dec 2020
DOIs
Publication statusPublished - 1 Feb 2021

Keywords

  • ChromlogD7.4
  • Fasted State Simulated Intestinal Fluid (FaSSIF)
  • general solubility equation (GSE)
  • kinetic solubility
  • physicochemical properties
  • simulated lung fluid (SLF)
  • thermodynamic solubility

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