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Piggyback Medicinal Chemistry for the
Development of Drugs for Malaria, African
Sleeping Sickness and Chagas’ Disease
Michael H. Gelb
Depts. of Chemistry and Biochemisry, University of Washington, Seattle, WA
98195 USA
We have been taking a “piggyback” approach for drug discovery of antiparasite agents. That is, we try to make use of drugs or drug candidates
that have already been developed by the pharmaceutical industry and extend
their use as anti-parasite agents. We have shown that inhibitors of protein
farnesyltransferase are potent cytoxic agents against P. falciparum and T.
brucei. The best compounds are the tetrahydroquinolines developed initially
at Bristol-Myers Squibb. We have taken a structure-guided approach for
developing these compounds as anti-parasite agents. These compounds
show potency for the inhibition of parasite growth in the low nanomolar
range. Some of the compounds are able to cure rodents infected with
malaria when given orally. However, the best compounds to date suffer from
rapid metabolism, and efforts are underway to improve the pharmacokinetics
of these compounds.
A spin-off of our studies is that the anti-cancer drug candidate
tipifarnib, being developed by Johnson and Johnson, kills T. cruzi in the low
nanomolar range. We have discovered that this compound targets lanosterol
14-demethylase, an enzyme required for ergosterol synthesis in the parasite.
We have recently prepared tipifarnib analogs that no longer bind to human
protein farnesyltransferase and still inhibit T. cruzi lanosterol 14demethylase. Compounds in this series show potency for killing parasites in
vitro in the sub-nanomolar range and are able to cure mice suffering from
acute Chagas’ disease. The pharmacokinetics and oral bioavailability of the
lead compounds are excellent, and our efforts have now shifted to
transitioning our best compounds through additional pre-clinical studies
needed to begin clinical trials.
Our studies will illustrate that it is possible to take a team effort at an
academic institution to discover drug candidates for the treatment of
neglected diseases.