Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)

Timothy M. Chapman; Simon A. Osborne; Nathalie Bouloc; Jonathan M. Large; Claire Wallace; Kristian Birchall; Keith H. Ansell; Hayley M. Jones; Debra Taylor; Barbara Clough; Judith L. Green; Anthony A. Holder

doi:10.1016/j.bmcl.2013.03.017

Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)

Timothy M. Chapman^*, Simon A. Osborne, Nathalie Bouloc, Jonathan M. Large, Claire Wallace, Kristian Birchall, Keith H. Ansell, Hayley M. Jones, Debra Taylor, Barbara Clough, Judith L. Green, Anthony A. Holder

^*Corresponding author for this work

Biosciences

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Abstract

A series of imidazopyridazines which are potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was identified from a high-throughput screen against the isolated enzyme. Subsequent exploration of the SAR and optimisation has yielded leading members which show promising in vitro anti-parasite activity along with good in vitro ADME and selectivity against human kinases. Initial in vivo testing has revealed good oral bioavailability in a mouse PK study and modest in vivo efficacy in a Plasmodium berghei mouse model of malaria.

Original language	English
Pages (from-to)	3064-3069
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2013.03.017
Publication status	Published - 15 May 2013

Bibliographical note

Funding Information:
We thank David Tickle and Sadhia Mahmood at MRCT for in vitro ADME, David Whalley for testing against PbCDPK1 and PvCDPK1 and Munira Grainger at NIMR for provision of parasites. We are grateful to the Medicines for Malaria Venture for providing support for this project, including Paul Willis, Didier Leroy and Simon Campbell for their input and Sergio Wittlin at the Swiss Tropical and Public Health Institute for conducting P. berghei in vivo efficacy studies. Mouse pharmacokinetic studies were performed by Pharmidex. A.A.H. is funded by the MRC ( U117532067 ) and the EU FP7 Grant agreement 242095 (EviMalar).

Keywords

Plasmodium falciparum Calcium-dependent protein kinase 1 Malaria Imidazopyridazine SAR

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2013.03.017

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Chapman, T. M., Osborne, S. A., Bouloc, N., Large, J. M., Wallace, C., Birchall, K., Ansell, K. H., Jones, H. M., Taylor, D., Clough, B., Green, J. L., & Holder, A. A. (2013). Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1). Bioorganic and Medicinal Chemistry Letters, 23(10), 3064-3069. https://doi.org/10.1016/j.bmcl.2013.03.017

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abstract = "A series of imidazopyridazines which are potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was identified from a high-throughput screen against the isolated enzyme. Subsequent exploration of the SAR and optimisation has yielded leading members which show promising in vitro anti-parasite activity along with good in vitro ADME and selectivity against human kinases. Initial in vivo testing has revealed good oral bioavailability in a mouse PK study and modest in vivo efficacy in a Plasmodium berghei mouse model of malaria.",

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note = "Funding Information: We thank David Tickle and Sadhia Mahmood at MRCT for in vitro ADME, David Whalley for testing against PbCDPK1 and PvCDPK1 and Munira Grainger at NIMR for provision of parasites. We are grateful to the Medicines for Malaria Venture for providing support for this project, including Paul Willis, Didier Leroy and Simon Campbell for their input and Sergio Wittlin at the Swiss Tropical and Public Health Institute for conducting P. berghei in vivo efficacy studies. Mouse pharmacokinetic studies were performed by Pharmidex. A.A.H. is funded by the MRC ( U117532067 ) and the EU FP7 Grant agreement 242095 (EviMalar).",

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Chapman, TM, Osborne, SA, Bouloc, N, Large, JM, Wallace, C, Birchall, K, Ansell, KH, Jones, HM, Taylor, D, Clough, B, Green, JL & Holder, AA 2013, 'Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 10, pp. 3064-3069. https://doi.org/10.1016/j.bmcl.2013.03.017

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AU - Green, Judith L.

AU - Holder, Anthony A.

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Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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