Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis

Michael G. Thomas; Manu De Rycker; Myriam Ajakane; Sabrinia D. Crouch; Lorna Campbell; Alain Daugan; Gloria Fra; César Guerrero; Claire J. Mackenzie; Lorna MacLean; Sujatha Manthri; Franck Martin; Suzanne Norval; Maria Osuna-Cabello; Jennifer Riley; Yoko Shishikura; Juan Miguel-Siles; Frederick R. C. Simeons; Laste Stojanovski; John Thomas; Stephen Thompson; Raul F. Velasco; Jose M. Fiandor; Paul G. Wyatt; Kevin D. Read; Ian H. Gilbert; Timothy J. Miles

doi:10.1039/d0md00203h

Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis

Michael G. Thomas, Manu De Rycker, Myriam Ajakane, Sabrinia D. Crouch, Lorna Campbell, Alain Daugan, Gloria Fra, César Guerrero, Claire J. Mackenzie, Lorna MacLean, Sujatha Manthri, Franck Martin, Suzanne Norval, Maria Osuna-Cabello, Jennifer Riley, Yoko Shishikura, Juan Miguel-Siles, Frederick R. C. Simeons, Laste Stojanovski, John ThomasStephen Thompson, Raul F. Velasco, Jose M. Fiandor, Paul G. Wyatt, Kevin D. Read, Ian H. Gilbert, Timothy J. Miles

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Abstract

Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino-N-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL.

Original language	English
Pages (from-to)	1168-1177
Number of pages	10
Journal	RSC Medicinal Chemistry
Volume	11
Issue number	10
Early online date	6 Aug 2020
DOIs	https://doi.org/10.1039/d0md00203h
Publication status	Published - 21 Oct 2020

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A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. & Gilbert, I.
Wellcome Trust
1/01/13 → 30/09/15
Project: Research
Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)
Brenk, R., Fairlamb, A., Ferguson, M., Field, M., Gilbert, I., Gray, D., Hopkins, A., Horn, D., Read, K., Wyatt, P. & van Aalten, D.
Wellcome Trust
1/02/11 → 1/07/17
Project: Research

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Thomas, M. G., De Rycker, M., Ajakane, M., Crouch, S. D., Campbell, L., Daugan, A., Fra, G., Guerrero, C., Mackenzie, C. J., MacLean, L., Manthri, S., Martin, F., Norval, S., Osuna-Cabello, M., Riley, J., Shishikura, Y., Miguel-Siles, J., Simeons, F. R. C., Stojanovski, L., ... Miles, T. J. (2020). Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis. RSC Medicinal Chemistry, 11(10), 1168-1177. https://doi.org/10.1039/d0md00203h

Thomas, Michael G. ; De Rycker, Manu ; Ajakane, Myriam ; Crouch, Sabrinia D. ; Campbell, Lorna ; Daugan, Alain ; Fra, Gloria ; Guerrero, César ; Mackenzie, Claire J. ; MacLean, Lorna ; Manthri, Sujatha ; Martin, Franck ; Norval, Suzanne ; Osuna-Cabello, Maria ; Riley, Jennifer ; Shishikura, Yoko ; Miguel-Siles, Juan ; Simeons, Frederick R. C. ; Stojanovski, Laste ; Thomas, John ; Thompson, Stephen ; Velasco, Raul F. ; Fiandor, Jose M. ; Wyatt, Paul G. ; Read, Kevin D. ; Gilbert, Ian H. ; Miles, Timothy J. / Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis. In: RSC Medicinal Chemistry. 2020 ; Vol. 11, No. 10. pp. 1168-1177.

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title = "Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis",

abstract = "Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino-N-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL.",

author = "Thomas, {Michael G.} and {De Rycker}, Manu and Myriam Ajakane and Crouch, {Sabrinia D.} and Lorna Campbell and Alain Daugan and Gloria Fra and C{\'e}sar Guerrero and Mackenzie, {Claire J.} and Lorna MacLean and Sujatha Manthri and Franck Martin and Suzanne Norval and Maria Osuna-Cabello and Jennifer Riley and Yoko Shishikura and Juan Miguel-Siles and Simeons, {Frederick R. C.} and Laste Stojanovski and John Thomas and Stephen Thompson and Velasco, {Raul F.} and Fiandor, {Jose M.} and Wyatt, {Paul G.} and Read, {Kevin D.} and Gilbert, {Ian H.} and Miles, {Timothy J.}",

note = "Funding for this work was provided by Wellcome (nos. 092340 and 100476",

year = "2020",

month = oct,

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doi = "10.1039/d0md00203h",

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Thomas, MG , De Rycker, M, Ajakane, M, Crouch, SD, Campbell, L, Daugan, A, Fra, G, Guerrero, C, Mackenzie, CJ , MacLean, L , Manthri, S, Martin, F, Norval, S , Osuna-Cabello, M , Riley, J , Shishikura, Y, Miguel-Siles, J, Simeons, FRC , Stojanovski, L , Thomas, J , Thompson, S, Velasco, RF, Fiandor, JM, Wyatt, PG , Read, KD , Gilbert, IH & Miles, TJ 2020, 'Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis', RSC Medicinal Chemistry, vol. 11, no. 10, pp. 1168-1177. https://doi.org/10.1039/d0md00203h

Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis. / Thomas, Michael G.; De Rycker, Manu; Ajakane, Myriam; Crouch, Sabrinia D.; Campbell, Lorna; Daugan, Alain; Fra, Gloria; Guerrero, César; Mackenzie, Claire J.; MacLean, Lorna ; Manthri, Sujatha; Martin, Franck; Norval, Suzanne ; Osuna-Cabello, Maria ; Riley, Jennifer ; Shishikura, Yoko; Miguel-Siles, Juan; Simeons, Frederick R. C.; Stojanovski, Laste ; Thomas, John ; Thompson, Stephen; Velasco, Raul F.; Fiandor, Jose M.; Wyatt, Paul G.; Read, Kevin D.; Gilbert, Ian H. (Lead / Corresponding author); Miles, Timothy J. (Lead / Corresponding author).

In: RSC Medicinal Chemistry, Vol. 11, No. 10, 21.10.2020, p. 1168-1177.

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

TY - JOUR

T1 - Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis

AU - Thomas, Michael G.

AU - De Rycker, Manu

AU - Ajakane, Myriam

AU - Crouch, Sabrinia D.

AU - Campbell, Lorna

AU - Daugan, Alain

AU - Fra, Gloria

AU - Guerrero, César

AU - Mackenzie, Claire J.

AU - MacLean, Lorna

AU - Manthri, Sujatha

AU - Martin, Franck

AU - Norval, Suzanne

AU - Osuna-Cabello, Maria

AU - Riley, Jennifer

AU - Shishikura, Yoko

AU - Miguel-Siles, Juan

AU - Simeons, Frederick R. C.

AU - Stojanovski, Laste

AU - Thomas, John

AU - Thompson, Stephen

AU - Velasco, Raul F.

AU - Fiandor, Jose M.

AU - Wyatt, Paul G.

AU - Read, Kevin D.

AU - Gilbert, Ian H.

AU - Miles, Timothy J.

N1 - Funding for this work was provided by Wellcome (nos. 092340 and 100476

PY - 2020/10/21

Y1 - 2020/10/21

N2 - Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino-N-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL.

AB - Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino-N-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL.

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U2 - 10.1039/d0md00203h

DO - 10.1039/d0md00203h

M3 - Article

VL - 11

SP - 1168

EP - 1177

JO - RSC Medicinal Chemistry

JF - RSC Medicinal Chemistry

SN - 2632-8682

IS - 10

ER -

Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis

Abstract

Access to Document

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Cite this