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Princeton, NJ, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 0.00 | Year: 2002

DESCRIPTION (Provided by applicant): Plasmodium falciparum is the parasitic protozoan responsible for fatal malaria in humans. It causes about 300 million clinical case of malaria and 2-3 million deaths annually. There is no vaccine against malaria, so selection of drug resistant malaria parasites has been a major factor in increased malaria morbidity and mortality in the last two decades. The few drugs that have been developed are too expensive for routine use in malaria treatment in most developing countries where the main burden of disease is felt. Inhibitors of the enzyme dihydrofolate reductase (DHFR) like pyrimethamine have been excellent antimalarials, but point mutations in the target gene compromised its effectiveness. The PS series of drugs are biguanides that are metabolized to triazines that also inhibit the P. falciparum DHFR. In Phase I, we have shown that these triazines do not show cross-resistance to any of the previously tested inhibitors of the P. falciparum DHFR, pyrimethamine, cycloguanil or chlorcycloguanil. In addition, we have recently discovered that these compounds are effective inhibitors of the DHFR enzyme from P. vivax, the most prevalent human malaria parasite. A clinical candidate has been selected based on 90 day oral studies in mice. This proposal is to support the preclinical safety assessment to bring this candidate to the clinic, to continue the yeast genetics program providing field monitoring for the development of resistance, and to extend the mechanism of action studies.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 100.00K | Year: 1999

N/A


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 50.00K | Year: 1991

THE RESEARCH IS DESIGNED TO DEVELOP AN IMPROVED SYNTHETIC METHOD FOR THE PRODUCTION OF A NEW BIOEFFICIENT DERIVATIVE OF AN ORALLY ACTIVE IRON CHELATOR FOR THE TREATMENT OF IRON OVERLOAD. IN PHASE I HUMAN TRIALS, THE PARENT DRUG (GIVEN ORALLY IN CAPSULES) PRODUCED AN AMOUNT OF IRON EXCRETION THAT WOULD BE CLINICALLY USEFUL IN THE TREATMENT OF NON- TRANSFUSION-DEPENDENT PATIENTS WITH IRON-LOADING ANEMIAS. THE BIOEFFICIENCY OF THE PARENT FORMULATION WAS MUCH LESS THAN THAT EXPECTED FROM ANIMAL STUDIES WITH THE PARENT DRUG GIVEN IN SOLUTION. HYPOTHESIZING THAT THE LIMITED BIOEFFICIENCY OBSERVED IN THE HUMAN STUDIES WAS THE RESULT OF THE POOR SOLUBILITY OF THE PARENT DRUG, WE HAVE DEVELOPED A PILOT-SCALE SYNTHESIS FOR THE PRODUCTION OF A NEW DERIVATIVE THAT IS MORE THAN 200-FOLD MORE WATER SOLUBLE. THIS NEW DRUG SHOULD SUBSTANTIALLY ENHANCE BIOEFFICIENCY AND MAKE THE CHELATOR CLINICALLY USEFUL IN THE TREATMENT OF TRANSFUSION-DEPENDENT PATIENTS. THE PHASE I PROJECT WILL DEVELOP A LARGER-SCALE METHOD OF SYNTHESIS OF THE NEW PRODRUG THAT WILL PERMIT THE PRODUCTION OF CLINICAL SUPPLIES FOR FURTHER HUMAN TRIALS DURING A PHASE II PROJECT.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.72M | Year: 2002

DESCRIPTION (Provided by applicant): Plasmodium falciparum is the parasitic protozoan responsible for fatal malaria in humans. It causes about 300 million clinical case of malaria and 2-3 million deaths annually. There is no vaccine against malaria, so selection of drug resistant malaria parasites has been a major factor in increased malaria morbidity and mortality in the last two decades. The few drugs that have been developed are too expensive for routine use in malaria treatment in most developing countries where the main burden of disease is felt. Inhibitors of the enzyme dihydrofolate reductase (DHFR) like pyrimethamine have been excellent antimalarials, but point mutations in the target gene compromised its effectiveness. The PS series of drugs are biguanides that are metabolized to triazines that also inhibit the P. falciparum DHFR. In Phase I, we have shown that these triazines do not show cross-resistance to any of the previously tested inhibitors of the P. falciparum DHFR, pyrimethamine, cycloguanil or chlorcycloguanil. In addition, we have recently discovered that these compounds are effective inhibitors of the DHFR enzyme from P. vivax, the most prevalent human malaria parasite. A clinical candidate has been selected based on 90 day oral studies in mice. This proposal is to support the preclinical safety assessment to bring this candidate to the clinic, to continue the yeast genetics program providing field monitoring for the development of resistance, and to extend the mechanism of action studies.

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