Pentamidine, a dication employed for decades to treat the tropical infectious leishmaniasis and African trypanosomiasis, remains useful for the treatment of antimony resistant leishmaniasis, primary stage human African trypanosomiasis, and as an important secondary drug for AIDS associated Pneumocystis carinii pneumonia. Poor oral bioavailability and toxicity has limited clinical use of pentamidine and related compounds. A prodrug approach has emerged that will allow one to develop new, less toxic, orally bioavailability drugs with improved activity. Diamidoximes have been designed that are readily absorbed after oral administration. The inactive prodrug is enzymatically converted to active diamidines that posses excellent activity and reduced toxicity. The specific aims of Phase I are to synthesize sufficient quantities of selected diamidoximes, to test antileishmanial and antimalarial activities in animal models, to examine acute toxicity and to initiate evaluation of pharmacokinetic properties. The objective of the Phase II period will be to have sufficient pharmacological and toxicological data for selected prodrugs and their active diamidines to permit rational selection of one or two compounds for the formal preclinical studies required for drug development. PROPOSED COMMERCIAL APPLICATION: Possible drugs for protozoal diseases.
NIH ExPorter
NIH ExPorter