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Optimization of an imidazopyridazine series of inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1).

Abstract：

:A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC50 values less than 10 nM and in vitro P. falciparum antiparasite EC50 values down to 12 nM, although these compounds did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compound profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compound exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Chapman TM,Osborne SA,Wallace C,Birchall K,Bouloc N,Jones HM,Ansell KH,Taylor DL,Clough B,Green JL,Holder AA

doi

10.1021/jm500342d

subject

Has Abstract

pub_date

2014-04-24 00:00:00

pages

3570-87

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

57

pub_type

杂志文章

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