Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides

Stephanie Russell; R. Rahmani; A.J. Jones; Harriet Newson; K. Neilde; I. Cotillo; M. Khajouei; L. Ferrins; Sana Qureishi; N. Nguyen; M.S. Martinez-Martinez; D.F. Weaver; M. Kaiser; J. Riley; J. Thomas; M. De Rycker; K.D. Read; Gavin Flematti; E. Ryan; S. Tanghe; A. Rodriguez; S.A. Charman; A. Kessler; V.M. Avery; J.B. Baell; Matthew Piggott

doi:10.1021/acs.jmedchem.6b00442

Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides

Stephanie Russell, R. Rahmani, A.J. Jones, Harriet Newson, K. Neilde, I. Cotillo, M. Khajouei, L. Ferrins, Sana Qureishi, N. Nguyen, M.S. Martinez-Martinez, D.F. Weaver, M. Kaiser, J. Riley, J. Thomas, M. De Rycker, K.D. Read, Gavin Flematti, E. Ryan, S. TangheA. Rodriguez, S.A. Charman, A. Kessler, V.M. Avery, J.B. Baell, Matthew Piggott

School of Molecular Sciences

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Abstract

© 2016 American Chemical Society.
The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.

Original language	English
Pages (from-to)	9686-9720
Number of pages	35
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	21
Early online date	22 Aug 2016
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00442
Publication status	Published - 10 Nov 2016

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10.1021/acs.jmedchem.6b00442

Russell et al., 2016 Hit-to-Lead optimisation
“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 author-directed link to Published Work http://pubsdc3.acs.org/articlesonrequest/AOR-4nEmmVUkuHScTb5KRFi6
Accepted author manuscript, 721 KBLicence: Unspecified

Discovery of Single Agents to Treat Chagas Disease and Human African Trypanosomiasis
Baell, J. (Investigator 01), Avery, V. (Investigator 02), Charman, S. (Investigator 03), Creek, D. (Investigator 04) & Piggott, M. (Investigator 05)
NHMRC National Health and Medical Research Council
1/01/15 → 31/12/17
Project: Research

Cite this

Russell, S., Rahmani, R., Jones, A. J., Newson, H., Neilde, K., Cotillo, I., Khajouei, M., Ferrins, L., Qureishi, S., Nguyen, N., Martinez-Martinez, M. S., Weaver, D. F., Kaiser, M., Riley, J., Thomas, J., De Rycker, M., Read, K. D., Flematti, G., Ryan, E., ... Piggott, M. (2016). Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides. Journal of Medicinal Chemistry, 59(21), 9686-9720. https://doi.org/10.1021/acs.jmedchem.6b00442

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title = "Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides",

abstract = "{\textcopyright} 2016 American Chemical Society.The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.",

author = "Stephanie Russell and R. Rahmani and A.J. Jones and Harriet Newson and K. Neilde and I. Cotillo and M. Khajouei and L. Ferrins and Sana Qureishi and N. Nguyen and M.S. Martinez-Martinez and D.F. Weaver and M. Kaiser and J. Riley and J. Thomas and {De Rycker}, M. and K.D. Read and Gavin Flematti and E. Ryan and S. Tanghe and A. Rodriguez and S.A. Charman and A. Kessler and V.M. Avery and J.B. Baell and Matthew Piggott",

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month = nov,

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doi = "10.1021/acs.jmedchem.6b00442",

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Russell, S, Rahmani, R, Jones, AJ, Newson, H, Neilde, K, Cotillo, I, Khajouei, M, Ferrins, L, Qureishi, S, Nguyen, N, Martinez-Martinez, MS, Weaver, DF, Kaiser, M, Riley, J, Thomas, J, De Rycker, M, Read, KD, Flematti, G, Ryan, E, Tanghe, S, Rodriguez, A, Charman, SA, Kessler, A, Avery, VM, Baell, JB & Piggott, M 2016, 'Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides', Journal of Medicinal Chemistry, vol. 59, no. 21, pp. 9686-9720. https://doi.org/10.1021/acs.jmedchem.6b00442

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T1 - Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides

AU - Russell, Stephanie

AU - Rahmani, R.

AU - Jones, A.J.

AU - Newson, Harriet

AU - Neilde, K.

AU - Cotillo, I.

AU - Khajouei, M.

AU - Ferrins, L.

AU - Qureishi, Sana

AU - Nguyen, N.

AU - Martinez-Martinez, M.S.

AU - Weaver, D.F.

AU - Kaiser, M.

AU - Riley, J.

AU - Thomas, J.

AU - De Rycker, M.

AU - Read, K.D.

AU - Flematti, Gavin

AU - Ryan, E.

AU - Tanghe, S.

AU - Rodriguez, A.

AU - Charman, S.A.

AU - Kessler, A.

AU - Avery, V.M.

AU - Baell, J.B.

AU - Piggott, Matthew

PY - 2016/11/10

Y1 - 2016/11/10

N2 - © 2016 American Chemical Society.The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.

AB - © 2016 American Chemical Society.The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.

U2 - 10.1021/acs.jmedchem.6b00442

DO - 10.1021/acs.jmedchem.6b00442

M3 - Article

C2 - 27548560

SN - 0022-2623

VL - 59

SP - 9686

EP - 9720

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 21

ER -

Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides

Abstract

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Discovery of Single Agents to Treat Chagas Disease and Human African Trypanosomiasis

Cite this