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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:33

Article

Cosgrove, Brett^1,2  Down, Kenneth¹  Bertrand, Sophie¹  Tomkinson, Nicholas C. O.²  Barker, Michael D.¹ 

[1] GlaxoSmithKline Med Res Ctr, Med Chem, Stevenage, Herts, England

[2] Univ Strathclyde, Dept Pure & Appl Chem, Glasgow, Lanark, Scotland

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

DOI  :  10.1016/j.bmcl.2020.127752

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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