Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues

Jonathan M. Large; Simon A. Osborne; Ela Smiljanic-Hurley; Keith H. Ansell; Hayley M. Jones; Debra L. Taylor; Barbara Clough; Judith L. Green; Anthony A. Holder

doi:10.1016/j.bmcl.2013.08.010

Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues

Jonathan M. Large^*, Simon A. Osborne, Ela Smiljanic-Hurley, Keith H. Ansell, Hayley M. Jones, Debra L. Taylor, Barbara Clough, Judith L. Green, Anthony A. Holder

^*Corresponding author for this work

Biosciences

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34 Citations (Scopus)

Abstract

The structural diversity and SAR in a series of imidazopyridazine inhibitors of Plasmodium falciparum calcium dependent protein kinase 1 (PfCDPK1) has been explored and extended. The opportunity to further improve key ADME parameters by means of lowering log D was identified, and this was achieved by replacement of a six-membered (hetero)aromatic linker with a pyrazole. A short SAR study has delivered key examples with useful in vitro activity and ADME profiles, good selectivity against a human kinase panel and improved levels of lipophilic ligand efficiency. These new analogues thus provide a credible additional route to further development of the series.

Original language	English
Pages (from-to)	6019-6024
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	21
DOIs	https://doi.org/10.1016/j.bmcl.2013.08.010
Publication status	Published - 1 Nov 2013

Bibliographical note

Funding Information:
We thank David Tickle and Sadhia Mahmood (MRCT) for in vitro ADME data and Munira Grainger (NIMR) for provision of parasites. We are grateful to Medicines for Malaria Venture for supporting this project. A.A.H. is funded by the MRC ( U117532067 ) and the EU FP7 grant agreement 242095 (EviMalar).

Keywords

Calcium-dependent protein kinase 1
Imidazopyridazine
Malaria
Plasmodium falciparum
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.2013.08.010

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Large, J. M., Osborne, S. A., Smiljanic-Hurley, E., Ansell, K. H., Jones, H. M., Taylor, D. L., Clough, B., Green, J. L., & Holder, A. A. (2013). Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues. Bioorganic and Medicinal Chemistry Letters, 23(21), 6019-6024. https://doi.org/10.1016/j.bmcl.2013.08.010

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abstract = "The structural diversity and SAR in a series of imidazopyridazine inhibitors of Plasmodium falciparum calcium dependent protein kinase 1 (PfCDPK1) has been explored and extended. The opportunity to further improve key ADME parameters by means of lowering log D was identified, and this was achieved by replacement of a six-membered (hetero)aromatic linker with a pyrazole. A short SAR study has delivered key examples with useful in vitro activity and ADME profiles, good selectivity against a human kinase panel and improved levels of lipophilic ligand efficiency. These new analogues thus provide a credible additional route to further development of the series.",

keywords = "Calcium-dependent protein kinase 1, Imidazopyridazine, Malaria, Plasmodium falciparum, SAR",

author = "Large, {Jonathan M.} and Osborne, {Simon A.} and Ela Smiljanic-Hurley and Ansell, {Keith H.} and Jones, {Hayley M.} and Taylor, {Debra L.} and Barbara Clough and Green, {Judith L.} and Holder, {Anthony A.}",

note = "Funding Information: We thank David Tickle and Sadhia Mahmood (MRCT) for in vitro ADME data and Munira Grainger (NIMR) for provision of parasites. We are grateful to Medicines for Malaria Venture for supporting this project. A.A.H. is funded by the MRC ( U117532067 ) and the EU FP7 grant agreement 242095 (EviMalar). ",

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doi = "10.1016/j.bmcl.2013.08.010",

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Large, JM, Osborne, SA, Smiljanic-Hurley, E, Ansell, KH, Jones, HM, Taylor, DL, Clough, B, Green, JL & Holder, AA 2013, 'Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 21, pp. 6019-6024. https://doi.org/10.1016/j.bmcl.2013.08.010

Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues. / Large, Jonathan M.; Osborne, Simon A.; Smiljanic-Hurley, Ela et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 21, 01.11.2013, p. 6019-6024.

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

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AU - Large, Jonathan M.

AU - Osborne, Simon A.

AU - Smiljanic-Hurley, Ela

AU - Ansell, Keith H.

AU - Jones, Hayley M.

AU - Taylor, Debra L.

AU - Clough, Barbara

AU - Green, Judith L.

AU - Holder, Anthony A.

N1 - Funding Information: We thank David Tickle and Sadhia Mahmood (MRCT) for in vitro ADME data and Munira Grainger (NIMR) for provision of parasites. We are grateful to Medicines for Malaria Venture for supporting this project. A.A.H. is funded by the MRC ( U117532067 ) and the EU FP7 grant agreement 242095 (EviMalar).

PY - 2013/11/1

Y1 - 2013/11/1

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Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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