Volume 13 Supplement 1

Challenges in malaria research: Core science and innovation

Open Access

Latter-stage preclinical developmental work on PL69/DM1157

  • David Peyton1, 2
Malaria Journal201413(Suppl 1):P70

https://doi.org/10.1186/1475-2875-13-S1-P70

Published: 22 September 2014

The drug class we originally termed ‘Reversed Chloroquines’ has been assessed, via SAR, to select a candidate for preclinical evaluation. Such molecules were originally designed to function like the late-20th century Gold-standard, chloroquine, but with an appendage that intentionally inhibits resistance. Thus, PL69/DM1157 was subjected to screening, beginning with potency against many laboratory-adapted strains of chloroquine-resistant P. falciparum and in vivo efficacy in mice. PL69/DM1157, having structural features in common with chloroquine, might have cardiac effects, so we evaluated for hERG interaction, but more rigorously in a guinea pig electrocardiogram model. The results indicated the cardiac safety to be similar to chloroquine.

Academic collaborators have subjected PL69/DM1157 to clinical isolates of highly resistant P. falciparum, as well as to P. vivax strains. A chloroquine-resistant strain of P. falciparum was also subjected to PL69/DM1157 pressure for over two years in an unsuccessful attempt to increase IC50.

The project has now progressed through off-target evaluations, in vitro toxicity assessments, and rat preclinical toxicity tests. The molecule has been synthesized under GLP certification, without chlorinated solvents or any chromatographic steps to >99% purity, at sufficient scale to permit final toxicity evaluation in a second species, as well as in a Phase-I clinical trial, using the same batch.

This work also demonstrates how collaboration between a university and a start-up company can be an alternative pathway to bring a neglected-disease drug through the necessary drug development steps. The experience gained through this and other malaria work has enabled the company to begin collaborative work on drug-resistant bacterial diseases as well.

Authors’ Affiliations

(1)
Portland State University
(2)
DesignMedix, Inc

Copyright

© Peyton; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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