Two analogues of fenarimol show curative activity in an experimental model of chagas disease

M. Keenan; J.H. Chaplin; P.W. Alexander; M.J. Abbott; W.M. Best; Andrea Khong; A.M.C. Botero; C.J. Perez; S.M. Cornwall; R.A. Thompson; K.L. White; D.M. Shackleford; M. Koltun; F.C.K. Chiu; J. Morizzi; E.W. Ryan; M. Campbell; T.W. Von Geldern; I. Scandale; E. Chatelain; S.A. Charman

doi:10.1021/jm401610c

Two analogues of fenarimol show curative activity in an experimental model of chagas disease

M. Keenan, J.H. Chaplin, P.W. Alexander, M.J. Abbott, W.M. Best, Andrea Khong, A.M.C. Botero, C.J. Perez, S.M. Cornwall, R.A. Thompson, K.L. White, D.M. Shackleford, M. Koltun, F.C.K. Chiu, J. Morizzi, E.W. Ryan, M. Campbell, T.W. Von Geldern, I. Scandale, E. ChatelainS.A. Charman

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

41 Citations (Scopus)

Abstract

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development. © 2013 American Chemical Society.

Original language	English
Pages (from-to)	10158-10170
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	24
DOIs	https://doi.org/10.1021/jm401610c
Publication status	Published - 2013

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Keenan, M., Chaplin, J. H., Alexander, P. W., Abbott, M. J., Best, W. M., Khong, A., Botero, A. M. C., Perez, C. J., Cornwall, S. M., Thompson, R. A., White, K. L., Shackleford, D. M., Koltun, M., Chiu, F. C. K., Morizzi, J., Ryan, E. W., Campbell, M., Von Geldern, T. W., Scandale, I., ... Charman, S. A. (2013). Two analogues of fenarimol show curative activity in an experimental model of chagas disease. Journal of Medicinal Chemistry, 56(24), 10158-10170. https://doi.org/10.1021/jm401610c

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title = "Two analogues of fenarimol show curative activity in an experimental model of chagas disease",

abstract = "Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development. {\textcopyright} 2013 American Chemical Society.",

author = "M. Keenan and J.H. Chaplin and P.W. Alexander and M.J. Abbott and W.M. Best and Andrea Khong and A.M.C. Botero and C.J. Perez and S.M. Cornwall and R.A. Thompson and K.L. White and D.M. Shackleford and M. Koltun and F.C.K. Chiu and J. Morizzi and E.W. Ryan and M. Campbell and {Von Geldern}, T.W. and I. Scandale and E. Chatelain and S.A. Charman",

year = "2013",

doi = "10.1021/jm401610c",

language = "English",

volume = "56",

pages = "10158--10170",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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Keenan, M, Chaplin, JH, Alexander, PW, Abbott, MJ, Best, WM, Khong, A, Botero, AMC, Perez, CJ, Cornwall, SM, Thompson, RA, White, KL, Shackleford, DM, Koltun, M, Chiu, FCK, Morizzi, J, Ryan, EW, Campbell, M, Von Geldern, TW, Scandale, I, Chatelain, E & Charman, SA 2013, 'Two analogues of fenarimol show curative activity in an experimental model of chagas disease', Journal of Medicinal Chemistry, vol. 56, no. 24, pp. 10158-10170. https://doi.org/10.1021/jm401610c

TY - JOUR

T1 - Two analogues of fenarimol show curative activity in an experimental model of chagas disease

AU - Keenan, M.

AU - Chaplin, J.H.

AU - Alexander, P.W.

AU - Abbott, M.J.

AU - Best, W.M.

AU - Khong, Andrea

AU - Botero, A.M.C.

AU - Perez, C.J.

AU - Cornwall, S.M.

AU - Thompson, R.A.

AU - White, K.L.

AU - Shackleford, D.M.

AU - Koltun, M.

AU - Chiu, F.C.K.

AU - Morizzi, J.

AU - Ryan, E.W.

AU - Campbell, M.

AU - Von Geldern, T.W.

AU - Scandale, I.

AU - Chatelain, E.

AU - Charman, S.A.

PY - 2013

Y1 - 2013

N2 - Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development. © 2013 American Chemical Society.

AB - Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development. © 2013 American Chemical Society.

U2 - 10.1021/jm401610c

DO - 10.1021/jm401610c

M3 - Article

C2 - 24304150

SN - 0022-2623

VL - 56

SP - 10158

EP - 10170

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Two analogues of fenarimol show curative activity in an experimental model of chagas disease

Abstract

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