Spirotetrahydro β-carbolines (spiroindolones): A new class of potent and orally efficacious compounds for the treatment of malaria

Bryan K.S. Yeung; Bin Zou; Matthias Rottmann; Suresh B. Lakshminarayana; Shi Hua Ang; Seh Yong Leong; Jocelyn Tan; Josephine Wong; Sonja Keller-Maerki; Christoph Fischli; Anne Goh; Esther K. Schmitt; Philipp Krastel; Eric Francotte; Kelli Kuhen; David Plouffe; Kerstin Henson; Trixie Wagner; Elizabeth A. Winzeler; Frank Petersen; Reto Brun; Veronique Dartois; Thierry T. Diagana; Thomas H. Keller

doi:10.1021/jm100410f

Spirotetrahydro β-carbolines (spiroindolones): A new class of potent and orally efficacious compounds for the treatment of malaria

Bryan K.S. Yeung, Bin Zou, Matthias Rottmann, Suresh B. Lakshminarayana, Shi Hua Ang, Seh Yong Leong, Jocelyn Tan, Josephine Wong, Sonja Keller-Maerki, Christoph Fischli, Anne Goh, Esther K. Schmitt, Philipp Krastel, Eric Francotte, Kelli Kuhen, David Plouffe, Kerstin Henson, Trixie Wagner, Elizabeth A. Winzeler, Frank PetersenReto Brun, Veronique Dartois, Thierry T. Diagana, Thomas H. Keller

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377 Scopus citations

Abstract

The antiplasmodial activity of a series of spirotetrahydro β-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC₅₀ of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC₅₀ = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.

Original language	English (US)
Pages (from-to)	5155-5164
Number of pages	10
Journal	Journal of medicinal chemistry
Volume	53
Issue number	14
DOIs	https://doi.org/10.1021/jm100410f
State	Published - Jul 22 2010
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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Yeung, B. K. S., Zou, B., Rottmann, M., Lakshminarayana, S. B., Ang, S. H., Leong, S. Y., Tan, J., Wong, J., Keller-Maerki, S., Fischli, C., Goh, A., Schmitt, E. K., Krastel, P., Francotte, E., Kuhen, K., Plouffe, D., Henson, K., Wagner, T., Winzeler, E. A., ... Keller, T. H. (2010). Spirotetrahydro β-carbolines (spiroindolones): A new class of potent and orally efficacious compounds for the treatment of malaria. Journal of medicinal chemistry, 53(14), 5155-5164. https://doi.org/10.1021/jm100410f

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title = "Spirotetrahydro β-carbolines (spiroindolones): A new class of potent and orally efficacious compounds for the treatment of malaria",

abstract = "The antiplasmodial activity of a series of spirotetrahydro β-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC50 of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC50 = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.",

author = "Yeung, {Bryan K.S.} and Bin Zou and Matthias Rottmann and Lakshminarayana, {Suresh B.} and Ang, {Shi Hua} and Leong, {Seh Yong} and Jocelyn Tan and Josephine Wong and Sonja Keller-Maerki and Christoph Fischli and Anne Goh and Schmitt, {Esther K.} and Philipp Krastel and Eric Francotte and Kelli Kuhen and David Plouffe and Kerstin Henson and Trixie Wagner and Winzeler, {Elizabeth A.} and Frank Petersen and Reto Brun and Veronique Dartois and Diagana, {Thierry T.} and Keller, {Thomas H.}",

year = "2010",

month = jul,

day = "22",

doi = "10.1021/jm100410f",

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Yeung, BKS, Zou, B, Rottmann, M, Lakshminarayana, SB, Ang, SH, Leong, SY, Tan, J, Wong, J, Keller-Maerki, S, Fischli, C, Goh, A, Schmitt, EK, Krastel, P, Francotte, E, Kuhen, K, Plouffe, D, Henson, K, Wagner, T, Winzeler, EA, Petersen, F, Brun, R, Dartois, V, Diagana, TT & Keller, TH 2010, 'Spirotetrahydro β-carbolines (spiroindolones): A new class of potent and orally efficacious compounds for the treatment of malaria', Journal of medicinal chemistry, vol. 53, no. 14, pp. 5155-5164. https://doi.org/10.1021/jm100410f

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AU - Yeung, Bryan K.S.

AU - Zou, Bin

AU - Rottmann, Matthias

AU - Lakshminarayana, Suresh B.

AU - Ang, Shi Hua

AU - Leong, Seh Yong

AU - Tan, Jocelyn

AU - Wong, Josephine

AU - Keller-Maerki, Sonja

AU - Fischli, Christoph

AU - Goh, Anne

AU - Schmitt, Esther K.

AU - Krastel, Philipp

AU - Francotte, Eric

AU - Kuhen, Kelli

AU - Plouffe, David

AU - Henson, Kerstin

AU - Wagner, Trixie

AU - Winzeler, Elizabeth A.

AU - Petersen, Frank

AU - Brun, Reto

AU - Dartois, Veronique

AU - Diagana, Thierry T.

AU - Keller, Thomas H.

PY - 2010/7/22

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AB - The antiplasmodial activity of a series of spirotetrahydro β-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC50 of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC50 = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.

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Spirotetrahydro β-carbolines (spiroindolones): A new class of potent and orally efficacious compounds for the treatment of malaria

Abstract

All Science Journal Classification (ASJC) codes

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