Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)

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• 作者：Timothy M. Chapman ; Simon A. Osborne ; Claire Wallace ; Kristian Birchall ; Nathalie Bouloc ; Hayley M. Jones ; Keith H. Ansell ; Debra L. Taylor ; Barbara Clough ; Judith L. Green ; Anthony A. Holder
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3570-3587
• 全文大小：676K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

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.