A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria

Margaret A. Phillips, Karen White, Sreekanth Kokkonda, Xiaoyi Deng, John White, Farah El Mazouni, Kennan Marsh, Diana R. Tomchick, Krishne Manjalanagara, Kakali Rani Rudra, Grennady Wirjanata, Rintis Noviyanti, Ric N. Price, Jutta Marfurt, David Shackleford, Francis Chiu, Michael Campbell, Maria Belen Jimenez-Diaz, Santiago Ferrer Bazaga, Iñigo Angulo-Barturen & 1 others Susan Charman

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.

Original languageEnglish
Pages (from-to)945-957
Number of pages13
JournalACS Infectious Diseases
Volume2
Issue number12
DOIs
Publication statusPublished - 9 Dec 2016

Keywords

  • dihydroorotate dehydrogenase
  • malaria
  • Plasmodium
  • pyrimidine biosynthesis

Cite this

Phillips, Margaret A. ; White, Karen ; Kokkonda, Sreekanth ; Deng, Xiaoyi ; White, John ; El Mazouni, Farah ; Marsh, Kennan ; Tomchick, Diana R. ; Manjalanagara, Krishne ; Rudra, Kakali Rani ; Wirjanata, Grennady ; Noviyanti, Rintis ; Price, Ric N. ; Marfurt, Jutta ; Shackleford, David ; Chiu, Francis ; Campbell, Michael ; Jimenez-Diaz, Maria Belen ; Bazaga, Santiago Ferrer ; Angulo-Barturen, Iñigo ; Charman, Susan. / A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria. In: ACS Infectious Diseases. 2016 ; Vol. 2, No. 12. pp. 945-957.
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abstract = "The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.",
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author = "Phillips, {Margaret A.} and Karen White and Sreekanth Kokkonda and Xiaoyi Deng and John White and {El Mazouni}, Farah and Kennan Marsh and Tomchick, {Diana R.} and Krishne Manjalanagara and Rudra, {Kakali Rani} and Grennady Wirjanata and Rintis Noviyanti and Price, {Ric N.} and Jutta Marfurt and David Shackleford and Francis Chiu and Michael Campbell and Jimenez-Diaz, {Maria Belen} and Bazaga, {Santiago Ferrer} and I{\~n}igo Angulo-Barturen and Susan Charman",
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Phillips, MA, White, K, Kokkonda, S, Deng, X, White, J, El Mazouni, F, Marsh, K, Tomchick, DR, Manjalanagara, K, Rudra, KR, Wirjanata, G, Noviyanti, R, Price, RN, Marfurt, J, Shackleford, D, Chiu, F, Campbell, M, Jimenez-Diaz, MB, Bazaga, SF, Angulo-Barturen, I & Charman, S 2016, 'A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria', ACS Infectious Diseases, vol. 2, no. 12, pp. 945-957. https://doi.org/10.1021/acsinfecdis.6b00144

A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria. / Phillips, Margaret A.; White, Karen; Kokkonda, Sreekanth; Deng, Xiaoyi; White, John; El Mazouni, Farah; Marsh, Kennan; Tomchick, Diana R.; Manjalanagara, Krishne; Rudra, Kakali Rani; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N.; Marfurt, Jutta; Shackleford, David; Chiu, Francis; Campbell, Michael; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Charman, Susan.

In: ACS Infectious Diseases, Vol. 2, No. 12, 09.12.2016, p. 945-957.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Phillips, Margaret A.

AU - White, Karen

AU - Kokkonda, Sreekanth

AU - Deng, Xiaoyi

AU - White, John

AU - El Mazouni, Farah

AU - Marsh, Kennan

AU - Tomchick, Diana R.

AU - Manjalanagara, Krishne

AU - Rudra, Kakali Rani

AU - Wirjanata, Grennady

AU - Noviyanti, Rintis

AU - Price, Ric N.

AU - Marfurt, Jutta

AU - Shackleford, David

AU - Chiu, Francis

AU - Campbell, Michael

AU - Jimenez-Diaz, Maria Belen

AU - Bazaga, Santiago Ferrer

AU - Angulo-Barturen, Iñigo

AU - Charman, Susan

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N2 - The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.

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KW - dihydroorotate dehydrogenase

KW - malaria

KW - Plasmodium

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