Imidazolopiperazines: Hit to lead optimization of new antimalarial agents

Tao Wu; Advait Nagle; Kelli Kuhen; Kerstin Gagaring; Rachel Borboa; Caroline Francek; Zhong Chen; David Plouffe; Anne Goh; Suresh B. Lakshminarayana; Jeanette Wu; Hui Qing Ang; Peiting Zeng; Min Low Kang; William Tan; Maria Tan; Nicole Ye; Xuena Lin; Christopher Caldwell; Jared Ek; Suzanne Skolnik; Fenghua Liu; Jianling Wang; Jonathan Chang; Chun Li; Thomas Hollenbeck; Tove Tuntland; John Isbell; Christoph Fischli; Reto Brun; Matthias Rottmann; Veronique Dartois; Thomas Keller; Thierry Diagana; Elizabeth Winzeler; Richard Glynne; David C. Tully; Arnab K. Chatterjee

doi:10.1021/jm2003359

Imidazolopiperazines: Hit to lead optimization of new antimalarial agents

Tao Wu, Advait Nagle, Kelli Kuhen, Kerstin Gagaring, Rachel Borboa, Caroline Francek, Zhong Chen, David Plouffe, Anne Goh, Suresh B. Lakshminarayana, Jeanette Wu, Hui Qing Ang, Peiting Zeng, Min Low Kang, William Tan, Maria Tan, Nicole Ye, Xuena Lin, Christopher Caldwell, Jared EkSuzanne Skolnik, Fenghua Liu, Jianling Wang, Jonathan Chang, Chun Li, Thomas Hollenbeck, Tove Tuntland, John Isbell, Christoph Fischli, Reto Brun, Matthias Rottmann, Veronique Dartois, Thomas Keller, Thierry Diagana, Elizabeth Winzeler, Richard Glynne, David C. Tully, Arnab K. Chatterjee

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Abstract

Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.

Original language	English (US)
Pages (from-to)	5116-5130
Number of pages	15
Journal	Journal of medicinal chemistry
Volume	54
Issue number	14
DOIs	https://doi.org/10.1021/jm2003359
State	Published - Jul 28 2011
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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10.1021/jm2003359

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Wu, T., Nagle, A., Kuhen, K., Gagaring, K., Borboa, R., Francek, C., Chen, Z., Plouffe, D., Goh, A., Lakshminarayana, S. B., Wu, J., Ang, H. Q., Zeng, P., Kang, M. L., Tan, W., Tan, M., Ye, N., Lin, X., Caldwell, C., ... Chatterjee, A. K. (2011). Imidazolopiperazines: Hit to lead optimization of new antimalarial agents. Journal of medicinal chemistry, 54(14), 5116-5130. https://doi.org/10.1021/jm2003359

@article{5056d5548fe647af8ebfec9fd25cf23a,

title = "Imidazolopiperazines: Hit to lead optimization of new antimalarial agents",

abstract = "Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.",

author = "Tao Wu and Advait Nagle and Kelli Kuhen and Kerstin Gagaring and Rachel Borboa and Caroline Francek and Zhong Chen and David Plouffe and Anne Goh and Lakshminarayana, {Suresh B.} and Jeanette Wu and Ang, {Hui Qing} and Peiting Zeng and Kang, {Min Low} and William Tan and Maria Tan and Nicole Ye and Xuena Lin and Christopher Caldwell and Jared Ek and Suzanne Skolnik and Fenghua Liu and Jianling Wang and Jonathan Chang and Chun Li and Thomas Hollenbeck and Tove Tuntland and John Isbell and Christoph Fischli and Reto Brun and Matthias Rottmann and Veronique Dartois and Thomas Keller and Thierry Diagana and Elizabeth Winzeler and Richard Glynne and Tully, {David C.} and Chatterjee, {Arnab K.}",

year = "2011",

month = jul,

day = "28",

doi = "10.1021/jm2003359",

language = "English (US)",

volume = "54",

pages = "5116--5130",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "14",

}

Wu, T, Nagle, A, Kuhen, K, Gagaring, K, Borboa, R, Francek, C, Chen, Z, Plouffe, D, Goh, A, Lakshminarayana, SB, Wu, J, Ang, HQ, Zeng, P, Kang, ML, Tan, W, Tan, M, Ye, N, Lin, X, Caldwell, C, Ek, J, Skolnik, S, Liu, F, Wang, J, Chang, J, Li, C, Hollenbeck, T, Tuntland, T, Isbell, J, Fischli, C, Brun, R, Rottmann, M, Dartois, V, Keller, T, Diagana, T, Winzeler, E, Glynne, R, Tully, DC & Chatterjee, AK 2011, 'Imidazolopiperazines: Hit to lead optimization of new antimalarial agents', Journal of medicinal chemistry, vol. 54, no. 14, pp. 5116-5130. https://doi.org/10.1021/jm2003359

TY - JOUR

T1 - Imidazolopiperazines

T2 - Hit to lead optimization of new antimalarial agents

AU - Wu, Tao

AU - Nagle, Advait

AU - Kuhen, Kelli

AU - Gagaring, Kerstin

AU - Borboa, Rachel

AU - Francek, Caroline

AU - Chen, Zhong

AU - Plouffe, David

AU - Goh, Anne

AU - Lakshminarayana, Suresh B.

AU - Wu, Jeanette

AU - Ang, Hui Qing

AU - Zeng, Peiting

AU - Kang, Min Low

AU - Tan, William

AU - Tan, Maria

AU - Ye, Nicole

AU - Lin, Xuena

AU - Caldwell, Christopher

AU - Ek, Jared

AU - Skolnik, Suzanne

AU - Liu, Fenghua

AU - Wang, Jianling

AU - Chang, Jonathan

AU - Li, Chun

AU - Hollenbeck, Thomas

AU - Tuntland, Tove

AU - Isbell, John

AU - Fischli, Christoph

AU - Brun, Reto

AU - Rottmann, Matthias

AU - Dartois, Veronique

AU - Keller, Thomas

AU - Diagana, Thierry

AU - Winzeler, Elizabeth

AU - Glynne, Richard

AU - Tully, David C.

AU - Chatterjee, Arnab K.

PY - 2011/7/28

Y1 - 2011/7/28

N2 - Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.

AB - Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.

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U2 - 10.1021/jm2003359

DO - 10.1021/jm2003359

M3 - Article

C2 - 21644570

AN - SCOPUS:79960645150

SN - 0022-2623

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SP - 5116

EP - 5130

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 14

ER -

Imidazolopiperazines: Hit to lead optimization of new antimalarial agents

Abstract

All Science Journal Classification (ASJC) codes

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