Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi

Stephen Brand, Eun Jung Ko, Elisabet Viayna, Stephen Thompson, Daniel Spinks, Michael Thomas, Lars Sandberg, Amanda F. Francisco, Shiromani Jayawardhana, Victoria C. Smith, Chimed Jansen, Manu De Rycker, John Thomas, Lorna MacLean, Maria Osuna-Cabello, Jennifer Riley, Paul Scullion, Laste Stojanovski, Frederick R. C. Simeons, Ola EpemoluYoko Shishikura, Sabrinia D. Crouch, Tania S. Bakshi, Christopher J. Nixon, Iain H. Reid, Alan P. Hill, Tim Z. Underwood, Sean J. Hindley, Sharon A. Robinson, John M. Kelly, Jose M. Fiandor, Paul G. Wyatt, Maria Marco, Timothy J. Miles, Kevin D. Read, Ian H. Gilbert

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Abstract

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

Original languageEnglish
Pages (from-to)7284-7299
Number of pages16
JournalJournal of Medicinal Chemistry
Volume60
Issue number17
Early online date27 Aug 2017
DOIs
Publication statusPublished - 14 Sep 2017

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Triazoles
Trypanosoma cruzi
Parasites
Chagas Disease
Nifurtimox
Latin America
Solubility
Infection
Therapeutics

Cite this

Brand, Stephen ; Ko, Eun Jung ; Viayna, Elisabet ; Thompson, Stephen ; Spinks, Daniel ; Thomas, Michael ; Sandberg, Lars ; Francisco, Amanda F. ; Jayawardhana, Shiromani ; Smith, Victoria C. ; Jansen, Chimed ; De Rycker, Manu ; Thomas, John ; MacLean, Lorna ; Osuna-Cabello, Maria ; Riley, Jennifer ; Scullion, Paul ; Stojanovski, Laste ; Simeons, Frederick R. C. ; Epemolu, Ola ; Shishikura, Yoko ; Crouch, Sabrinia D. ; Bakshi, Tania S. ; Nixon, Christopher J. ; Reid, Iain H. ; Hill, Alan P. ; Underwood, Tim Z. ; Hindley, Sean J. ; Robinson, Sharon A. ; Kelly, John M. ; Fiandor, Jose M. ; Wyatt, Paul G. ; Marco, Maria ; Miles, Timothy J. ; Read, Kevin D. ; Gilbert, Ian H. / Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 17. pp. 7284-7299.
@article{c8402046f3ed48e28c4e242c0c947af3,
title = "Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi",
abstract = "Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.",
author = "Stephen Brand and Ko, {Eun Jung} and Elisabet Viayna and Stephen Thompson and Daniel Spinks and Michael Thomas and Lars Sandberg and Francisco, {Amanda F.} and Shiromani Jayawardhana and Smith, {Victoria C.} and Chimed Jansen and {De Rycker}, Manu and John Thomas and Lorna MacLean and Maria Osuna-Cabello and Jennifer Riley and Paul Scullion and Laste Stojanovski and Simeons, {Frederick R. C.} and Ola Epemolu and Yoko Shishikura and Crouch, {Sabrinia D.} and Bakshi, {Tania S.} and Nixon, {Christopher J.} and Reid, {Iain H.} and Hill, {Alan P.} and Underwood, {Tim Z.} and Hindley, {Sean J.} and Robinson, {Sharon A.} and Kelly, {John M.} and Fiandor, {Jose M.} and Wyatt, {Paul G.} and Maria Marco and Miles, {Timothy J.} and Read, {Kevin D.} and Gilbert, {Ian H.}",
note = "Funding for this work was provided by the Wellcome Trust (nos. 092340 and 100476)",
year = "2017",
month = "9",
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doi = "10.1021/acs.jmedchem.7b00463",
language = "English",
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Brand, S, Ko, EJ, Viayna, E, Thompson, S, Spinks, D, Thomas, M, Sandberg, L, Francisco, AF, Jayawardhana, S, Smith, VC, Jansen, C, De Rycker, M, Thomas, J, MacLean, L, Osuna-Cabello, M, Riley, J, Scullion, P, Stojanovski, L, Simeons, FRC, Epemolu, O, Shishikura, Y, Crouch, SD, Bakshi, TS, Nixon, CJ, Reid, IH, Hill, AP, Underwood, TZ, Hindley, SJ, Robinson, SA, Kelly, JM, Fiandor, JM, Wyatt, PG, Marco, M, Miles, TJ, Read, KD & Gilbert, IH 2017, 'Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi', Journal of Medicinal Chemistry, vol. 60, no. 17, pp. 7284-7299. https://doi.org/10.1021/acs.jmedchem.7b00463

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi. / Brand, Stephen; Ko, Eun Jung; Viayna, Elisabet; Thompson, Stephen; Spinks, Daniel; Thomas, Michael; Sandberg, Lars; Francisco, Amanda F.; Jayawardhana, Shiromani; Smith, Victoria C.; Jansen, Chimed; De Rycker, Manu; Thomas, John; MacLean, Lorna; Osuna-Cabello, Maria; Riley, Jennifer; Scullion, Paul; Stojanovski, Laste; Simeons, Frederick R. C.; Epemolu, Ola; Shishikura, Yoko; Crouch, Sabrinia D.; Bakshi, Tania S.; Nixon, Christopher J.; Reid, Iain H.; Hill, Alan P.; Underwood, Tim Z.; Hindley, Sean J.; Robinson, Sharon A.; Kelly, John M.; Fiandor, Jose M.; Wyatt, Paul G.; Marco, Maria; Miles, Timothy J. (Lead / Corresponding author); Read, Kevin D. (Lead / Corresponding author); Gilbert, Ian H. (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 60, No. 17, 14.09.2017, p. 7284-7299.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi

AU - Brand, Stephen

AU - Ko, Eun Jung

AU - Viayna, Elisabet

AU - Thompson, Stephen

AU - Spinks, Daniel

AU - Thomas, Michael

AU - Sandberg, Lars

AU - Francisco, Amanda F.

AU - Jayawardhana, Shiromani

AU - Smith, Victoria C.

AU - Jansen, Chimed

AU - De Rycker, Manu

AU - Thomas, John

AU - MacLean, Lorna

AU - Osuna-Cabello, Maria

AU - Riley, Jennifer

AU - Scullion, Paul

AU - Stojanovski, Laste

AU - Simeons, Frederick R. C.

AU - Epemolu, Ola

AU - Shishikura, Yoko

AU - Crouch, Sabrinia D.

AU - Bakshi, Tania S.

AU - Nixon, Christopher J.

AU - Reid, Iain H.

AU - Hill, Alan P.

AU - Underwood, Tim Z.

AU - Hindley, Sean J.

AU - Robinson, Sharon A.

AU - Kelly, John M.

AU - Fiandor, Jose M.

AU - Wyatt, Paul G.

AU - Marco, Maria

AU - Miles, Timothy J.

AU - Read, Kevin D.

AU - Gilbert, Ian H.

N1 - Funding for this work was provided by the Wellcome Trust (nos. 092340 and 100476)

PY - 2017/9/14

Y1 - 2017/9/14

N2 - Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

AB - Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

U2 - 10.1021/acs.jmedchem.7b00463

DO - 10.1021/acs.jmedchem.7b00463

M3 - Article

C2 - 28844141

VL - 60

SP - 7284

EP - 7299

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -