Discovery and Optimisation of a Compound Series active against Trypanosoma cruzi, the causative agent of Chagas’ Disease

Justin R. Harrison; Sandipan Sarkar; Shahienaz Hampton; Jennifer Riley; Laste Stojanovski; Christer Sahlberg; Pia Appelqvist; Jessey Erath; Vinodhini Mathan; Ana Rodriguez; Marcel Kaiser; Dolores Gonzalez Pacanowska; Kevin D. Read; Nils Gunnar Johansson; Ian H. Gilbert

doi:10.1021/acs.jmedchem.9b01852

Discovery and Optimisation of a Compound Series active against Trypanosoma cruzi, the causative agent of Chagas’ Disease

Justin R. Harrison, Sandipan Sarkar, Shahienaz Hampton, Jennifer Riley, Laste Stojanovski, Christer Sahlberg, Pia Appelqvist, Jessey Erath, Vinodhini Mathan, Ana Rodriguez, Marcel Kaiser, Dolores Gonzalez Pacanowska, Kevin D. Read, Nils Gunnar Johansson, Ian H. Gilbert (Lead / Corresponding author)

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Abstract

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments. In this work, we describe the optimization of a hit compound resulting from the phenotypic screen of a library of compounds against T. cruzi. The compound series was optimized to the level where it had satisfactory pharmacokinetics to allow an efficacy study in a mouse model of Chagas disease. We were able to demonstrate efficacy in this model, although further work is required to improve the potency and selectivity of this series.

Original language	English
Pages (from-to)	3066-3089
Number of pages	24
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	6
Early online date	5 Mar 2020
DOIs	https://doi.org/10.1021/acs.jmedchem.9b01852
Publication status	Published - 26 Mar 2020

ASJC Scopus subject areas

General Materials Science

UN SDGs

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

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10.1021/acs.jmedchem.9b01852

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This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review. To access the final edited and published work, see https://doi.org/10.1021/acs.jmedchem.9b01852.
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Cite this

Harrison, J. R., Sarkar, S., Hampton, S., Riley, J., Stojanovski, L., Sahlberg, C., Appelqvist, P., Erath, J., Mathan, V., Rodriguez, A., Kaiser, M., Pacanowska, D. G., Read, K. D., Johansson, N. G., & Gilbert, I. H. (2020). Discovery and Optimisation of a Compound Series active against Trypanosoma cruzi, the causative agent of Chagas’ Disease. Journal of Medicinal Chemistry, 63(6), 3066-3089. https://doi.org/10.1021/acs.jmedchem.9b01852

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abstract = "Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments. In this work, we describe the optimization of a hit compound resulting from the phenotypic screen of a library of compounds against T. cruzi. The compound series was optimized to the level where it had satisfactory pharmacokinetics to allow an efficacy study in a mouse model of Chagas disease. We were able to demonstrate efficacy in this model, although further work is required to improve the potency and selectivity of this series.",

author = "Harrison, {Justin R.} and Sandipan Sarkar and Shahienaz Hampton and Jennifer Riley and Laste Stojanovski and Christer Sahlberg and Pia Appelqvist and Jessey Erath and Vinodhini Mathan and Ana Rodriguez and Marcel Kaiser and Pacanowska, {Dolores Gonzalez} and Read, {Kevin D.} and Johansson, {Nils Gunnar} and Gilbert, {Ian H.}",

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Harrison, JR, Sarkar, S, Hampton, S, Riley, J , Stojanovski, L, Sahlberg, C, Appelqvist, P, Erath, J, Mathan, V, Rodriguez, A, Kaiser, M, Pacanowska, DG, Read, KD, Johansson, NG & Gilbert, IH 2020, 'Discovery and Optimisation of a Compound Series active against Trypanosoma cruzi, the causative agent of Chagas’ Disease', Journal of Medicinal Chemistry, vol. 63, no. 6, pp. 3066-3089. https://doi.org/10.1021/acs.jmedchem.9b01852

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AU - Harrison, Justin R.

AU - Sarkar, Sandipan

AU - Hampton, Shahienaz

AU - Riley, Jennifer

AU - Stojanovski, Laste

AU - Sahlberg, Christer

AU - Appelqvist, Pia

AU - Erath, Jessey

AU - Mathan, Vinodhini

AU - Rodriguez, Ana

AU - Kaiser, Marcel

AU - Pacanowska, Dolores Gonzalez

AU - Read, Kevin D.

AU - Johansson, Nils Gunnar

AU - Gilbert, Ian H.

PY - 2020/3/26

Y1 - 2020/3/26

N2 - Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments. In this work, we describe the optimization of a hit compound resulting from the phenotypic screen of a library of compounds against T. cruzi. The compound series was optimized to the level where it had satisfactory pharmacokinetics to allow an efficacy study in a mouse model of Chagas disease. We were able to demonstrate efficacy in this model, although further work is required to improve the potency and selectivity of this series.

AB - Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments. In this work, we describe the optimization of a hit compound resulting from the phenotypic screen of a library of compounds against T. cruzi. The compound series was optimized to the level where it had satisfactory pharmacokinetics to allow an efficacy study in a mouse model of Chagas disease. We were able to demonstrate efficacy in this model, although further work is required to improve the potency and selectivity of this series.

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U2 - 10.1021/acs.jmedchem.9b01852

DO - 10.1021/acs.jmedchem.9b01852

M3 - Article

C2 - 32134269

SN - 0022-2623

VL - 63

SP - 3066

EP - 3089

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 6

ER -

Discovery and Optimisation of a Compound Series active against Trypanosoma cruzi, the causative agent of Chagas’ Disease

Abstract

ASJC Scopus subject areas

UN SDGs

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