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

Bioorg Med Chem Lett. 2021 Feb 1:33:127752. doi: 10.1016/j.bmcl.2020.127752. Epub 2020 Dec 29.

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.

Keywords: ChromlogD(7.4); Fasted State Simulated Intestinal fluid (FaSSIF); General Solubility Equation (GSE); Kinetic solubility; Physicochemical properties; Simulated lung fluid (SLF); Thermodynamic solubility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / chemistry*
  • Molecular Structure
  • Nitrogen / chemistry*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Solubility
  • Thermodynamics*

Substances

  • Amides
  • Heterocyclic Compounds, 2-Ring
  • Pyrimidines
  • Nitrogen