Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity: Initial SAR and Assessment of In Vivo Activity

Michael Thomas; Manu De Rycker; Richard J. Wall; Daniel Spinks; Ola Epemolu; Sujatha Manthri; Suzanne Norval; Maria Osuna-Cabello; Stephen Patterson; Jennifer Riley; Frederick R. C. Simeons; Laste Stojanovski; John Thomas; Stephen Thompson; Claire Naylor; Jose M. Fiandor; Paul G. Wyatt; Maria Marco; Susan Wyllie; Kevin D. Read; Timothy J. Miles; Ian H. Gilbert

doi:10.1021/acs.jmedchem.0c00705

Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity: Initial SAR and Assessment of In Vivo Activity

Michael Thomas (Lead / Corresponding author), Manu De Rycker, Richard J. Wall, Daniel Spinks, Ola Epemolu, Sujatha Manthri, Suzanne Norval, Maria Osuna-Cabello, Stephen Patterson, Jennifer Riley, Frederick R. C. Simeons, Laste Stojanovski, John Thomas, Stephen Thompson, Claire Naylor, Jose M. Fiandor, Paul G. Wyatt, Maria Marco, Susan Wyllie, Kevin D. ReadTimothy J. Miles, Ian H. Gilbert (Lead / Corresponding author)

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

8 Citations (Scopus)

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Abstract

Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26,000 - 65,000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy and unsuitable dosing options. The need for new treatments is urgent and led to a collaboration between the Drugs for Neglected Diseases initiative (DNDi), GlaxoSmithKline (GSK) and the University of Dundee. An 8-hydroxynaphthyridine was identified as a start point and an early compound demonstrated weak efficacy in a mouse model of VL but was hampered by glucuronidation. Efforts to address this led to the development of compounds with improved in vitro profiles, but these were poorly tolerated in vivo. Investigation of the mode of action (MoA) demonstrated that activity was driven by sequestration of divalent metal cations, a mechanism which was likely to drive the poor tolerability. This highlights the importance of investigating MoA and pharmacokinetics at an early stage for phenotypically active series.

Original language	English
Pages (from-to)	9523-9539
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	17
Early online date	14 Jul 2020
DOIs	https://doi.org/10.1021/acs.jmedchem.0c00705
Publication status	Published - 10 Sept 2020

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.0c00705Licence: CC BY

Final Published VersionFinal published version, 1.8 MBLicence: CC BY

Cite this

Thomas, M., De Rycker, M., Wall, R. J., Spinks, D., Epemolu, O., Manthri, S., Norval, S., Osuna-Cabello, M., Patterson, S., Riley, J., Simeons, F. R. C., Stojanovski, L., Thomas, J., Thompson, S., Naylor, C., Fiandor, J. M., Wyatt, P. G., Marco, M., Wyllie, S., ... Gilbert, I. H. (2020). Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity: Initial SAR and Assessment of In Vivo Activity. Journal of Medicinal Chemistry, 63(17), 9523-9539. https://doi.org/10.1021/acs.jmedchem.0c00705

@article{66dda91e1d5b417f83ccdf404f14a9f1,

title = "Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity: Initial SAR and Assessment of In Vivo Activity",

abstract = "Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26,000 - 65,000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy and unsuitable dosing options. The need for new treatments is urgent and led to a collaboration between the Drugs for Neglected Diseases initiative (DNDi), GlaxoSmithKline (GSK) and the University of Dundee. An 8-hydroxynaphthyridine was identified as a start point and an early compound demonstrated weak efficacy in a mouse model of VL but was hampered by glucuronidation. Efforts to address this led to the development of compounds with improved in vitro profiles, but these were poorly tolerated in vivo. Investigation of the mode of action (MoA) demonstrated that activity was driven by sequestration of divalent metal cations, a mechanism which was likely to drive the poor tolerability. This highlights the importance of investigating MoA and pharmacokinetics at an early stage for phenotypically active series.",

author = "Michael Thomas and {De Rycker}, Manu and Wall, {Richard J.} and Daniel Spinks and Ola Epemolu and Sujatha Manthri and Suzanne Norval and Maria Osuna-Cabello and Stephen Patterson and Jennifer Riley and Simeons, {Frederick R. C.} and Laste Stojanovski and John Thomas and Stephen Thompson and Claire Naylor and Fiandor, {Jose M.} and Wyatt, {Paul G.} and Maria Marco and Susan Wyllie and Read, {Kevin D.} and Miles, {Timothy J.} and Gilbert, {Ian H.}",

note = "Funding: Wellcome Trust (nos. 092340 and 100476",

year = "2020",

month = sep,

day = "10",

doi = "10.1021/acs.jmedchem.0c00705",

language = "English",

volume = "63",

pages = "9523--9539",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "17",

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Thomas, M , De Rycker, M , Wall, RJ, Spinks, D, Epemolu, O, Manthri, S, Norval, S, Osuna-Cabello, M, Patterson, S, Riley, J , Simeons, FRC , Stojanovski, L , Thomas, J , Thompson, S , Naylor, C, Fiandor, JM, Wyatt, PG, Marco, M, Wyllie, S , Read, KD, Miles, TJ & Gilbert, IH 2020, 'Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity: Initial SAR and Assessment of In Vivo Activity', Journal of Medicinal Chemistry, vol. 63, no. 17, pp. 9523-9539. https://doi.org/10.1021/acs.jmedchem.0c00705

Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity: Initial SAR and Assessment of In Vivo Activity. / Thomas, Michael (Lead / Corresponding author); De Rycker, Manu ; Wall, Richard J. et al.
In: Journal of Medicinal Chemistry, Vol. 63, No. 17, 10.09.2020, p. 9523-9539.

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

TY - JOUR

T1 - Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity

T2 - Initial SAR and Assessment of In Vivo Activity

AU - Thomas, Michael

AU - De Rycker, Manu

AU - Wall, Richard J.

AU - Spinks, Daniel

AU - Epemolu, Ola

AU - Manthri, Sujatha

AU - Norval, Suzanne

AU - Osuna-Cabello, Maria

AU - Patterson, Stephen

AU - Riley, Jennifer

AU - Simeons, Frederick R. C.

AU - Stojanovski, Laste

AU - Thomas, John

AU - Thompson, Stephen

AU - Naylor, Claire

AU - Fiandor, Jose M.

AU - Wyatt, Paul G.

AU - Marco, Maria

AU - Wyllie, Susan

AU - Read, Kevin D.

AU - Miles, Timothy J.

AU - Gilbert, Ian H.

N1 - Funding: Wellcome Trust (nos. 092340 and 100476

PY - 2020/9/10

Y1 - 2020/9/10

N2 - Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26,000 - 65,000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy and unsuitable dosing options. The need for new treatments is urgent and led to a collaboration between the Drugs for Neglected Diseases initiative (DNDi), GlaxoSmithKline (GSK) and the University of Dundee. An 8-hydroxynaphthyridine was identified as a start point and an early compound demonstrated weak efficacy in a mouse model of VL but was hampered by glucuronidation. Efforts to address this led to the development of compounds with improved in vitro profiles, but these were poorly tolerated in vivo. Investigation of the mode of action (MoA) demonstrated that activity was driven by sequestration of divalent metal cations, a mechanism which was likely to drive the poor tolerability. This highlights the importance of investigating MoA and pharmacokinetics at an early stage for phenotypically active series.

AB - Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26,000 - 65,000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy and unsuitable dosing options. The need for new treatments is urgent and led to a collaboration between the Drugs for Neglected Diseases initiative (DNDi), GlaxoSmithKline (GSK) and the University of Dundee. An 8-hydroxynaphthyridine was identified as a start point and an early compound demonstrated weak efficacy in a mouse model of VL but was hampered by glucuronidation. Efforts to address this led to the development of compounds with improved in vitro profiles, but these were poorly tolerated in vivo. Investigation of the mode of action (MoA) demonstrated that activity was driven by sequestration of divalent metal cations, a mechanism which was likely to drive the poor tolerability. This highlights the importance of investigating MoA and pharmacokinetics at an early stage for phenotypically active series.

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U2 - 10.1021/acs.jmedchem.0c00705

DO - 10.1021/acs.jmedchem.0c00705

M3 - Article

C2 - 32663005

SN - 0022-2623

VL - 63

SP - 9523

EP - 9539

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 17

ER -

Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity: Initial SAR and Assessment of In Vivo Activity

Abstract

ASJC Scopus subject areas

UN SDGs

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Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Cite this

Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity: Initial SAR and Assessment of In Vivo Activity

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Cite this