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

doi:10.1016/j.bmcl.2020.127752

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

Pure And Applied Chemistry

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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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 language	English
Article number	127752
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	33
Early online date	29 Dec 2020
DOIs	https://doi.org/10.1016/j.bmcl.2020.127752
Publication status	Published - 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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10.1016/j.bmcl.2020.127752

Cosgrove-etal-BMCL-2021-Investigating-the-effects-of-the-core-nitrogen-atom-configurationAccepted author manuscript, 460 KBLicence: CC BY-NC-ND 4.0

1 Active

Accelerated Discovery and Development of New Medicines: Prosperity Partnership for a Healthier Nation
Kerr, W., Brown, C., Florence, A., Jamieson, C., Johnston, B., Murphy, J., Palmer, D. & Tomkinson, N.
EPSRC (Engineering and Physical Sciences Research Council)
1/01/19 → 30/09/24
Project: Research

Cite this

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

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

author = "Brett Cosgrove and Kenneth Down and Sophie Bertrand and Tomkinson, {Nicholas C.O.} and Barker, {Michael D.}",

year = "2021",

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doi = "10.1016/j.bmcl.2020.127752",

language = "English",

volume = "33",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Investigating the effects of the core nitrogen atom configuration on the thermodynamic solubility of 6,5-bicyclic heterocycles

AU - Cosgrove, Brett

AU - Down, Kenneth

AU - Bertrand, Sophie

AU - Tomkinson, Nicholas C.O.

AU - Barker, Michael D.

PY - 2021/2/1

Y1 - 2021/2/1

N2 - 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.

AB - 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.

KW - ChromlogD7.4

KW - Fasted State Simulated Intestinal Fluid (FaSSIF)

KW - general solubility equation (GSE)

KW - kinetic solubility

KW - physicochemical properties

KW - simulated lung fluid (SLF)

KW - thermodynamic solubility

U2 - 10.1016/j.bmcl.2020.127752

DO - 10.1016/j.bmcl.2020.127752

M3 - Article

VL - 33

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

M1 - 127752

ER -

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

Abstract

Keywords

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Projects

Accelerated Discovery and Development of New Medicines: Prosperity Partnership for a Healthier Nation

Cite this

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