DesignMedix has developed a novel class of compounds to address the pressing need for an orally available, inexpensive drug to counter the spread of chloroquine-resistant malaria. Preliminary data showed that this novel class of molecules, called """"""""reversed chloroquines"""""""" (RCQs), acts against both chloroquine- resistant and chloroquine-sensitive malaria in vitro. In our Phase I study, we demonstrated the feasibility of this approach both in vitro and in an in vivo animal model, showing that compounds were orally available, had in vivo effectiveness similar to that of chloroquine, and were very effective against chloroquine-resistant human malaria parasites in vitro. The goal of this Phase II project is to choose and move specific RCQ drug candidates into preclinical studies to advance commercialization of a therapeutic product. In addition to focusing on the clearly-identified lead compounds from the Phase I, we will enlarge the initial panel of RCQ structures based on results from that initial feasibility study, and test them against chloroquine-sensitive and chloroquine-resistant malaria in human red blood cells in vitro, as well as for other in vitro tests for solubility, central nervous system receptor activity, mutagenic activity, and cytotoxicity. Oral availability will begin with mice, as will in vivo toxicity evaluations. The most promising of the original and modified RCQ candidates will be moved forward toward preclinical study through evaluation in animal models for their pharmacokinetics and metabolism. We expect that at the conclusion of the Phase II project, one or more lead RCQ drug candidates will be ready for study in a primate model system of chloroquine-resistant malaria, the final step before full preclinical GLP toxicity and ADME studies for filing an IND application for human clinical studies. DesignMedix is directing this study specifically against P. falciparum, the most problematic human malaria variant, but RCQs also should be effective against the other human malarias. The product addresses market opportunities that include large endemic markets with international non-profit and government buyers, smaller but substantial markets for military and travelers, as well as private markets in developing countries such as India and China. Further development of the product will be carried out with resources from multiple sources, including equity investment, company and global health non-profit partnerships, and additional grant funding.

Public Health Relevance

Malaria is a disease that infects almost half a billion people annually and kills between one and three million people, most of whom are either children or pregnant women. Malaria is increasing, partly because the parasite that causes malaria has evolved into strains that are resistant to our best drugs for treating the disease. This work is to develop further promising lead candidates from a new class of drugs, `reversed chloroquines'(RCQs), designed to overcome this resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
Project #
5R42AI072923-03
Application #
7788793
Study Section
Special Emphasis Panel (ZRG1-IDM-Q (10))
Program Officer
Rogers, Martin J
Project Start
2007-03-15
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$644,773
Indirect Cost
Name
Designmedix, Inc.
Department
Type
DUNS #
623389009
City
Portland
State
OR
Country
United States
Zip Code
97201
Peyton, David H (2012) Reversed chloroquine molecules as a strategy to overcome resistance in malaria. Curr Top Med Chem 12:400-7
Andrews, Simeon; Burgess, Steven J; Skaalrud, Deborah et al. (2010) Reversal agent and linker variants of reversed chloroquines: activities against Plasmodium falciparum. J Med Chem 53:916-9
Burgess, Steven J; Kelly, Jane X; Shomloo, Shawheen et al. (2010) Synthesis, structure-activity relationship, and mode-of-action studies of antimalarial reversed chloroquine compounds. J Med Chem 53:6477-89