Grants and Contracts Details
Description
Leishmania parasites infect an estimated 12 million individuals, and no satisfactory treatments are
yet available. This proposal will advance 3 scaffolds that have emerged from a phenotypic screen for
development of leads towards novel effective orally-bioavailable drugs against leishmaniasis. Summary. A
previous phenotypic screen against the disease-causing intracellular amastigote stage of Leishmania parasites
has identified 3 chemical scaffolds with potent efficacy against amastigotes. Each hit compound exhibits
nanomolar efficacy against amastigotes growing in tissue culture macrophages and has physical and chemical
properties suggesting promise for development of a novel orally bioavailable drug. Analogs of each scaffold will
be prepared and tested for efficacy against amastigotes in vitro, optimal
absorption/distribution/metabolism/excretion/toxicity (ADMET) profiles, acceptable in vivo pharmacokinetics
(PK), and efficacy in controlling disease in a murine model of visceral leishmaniasis. Following establishment
of initial structure-activity relationships, an extensive medicinal chemistry program will be undertaken to
develop analogs with the best overall properties for orally bioavailable drugs and to improve upon any potential
deficits that emerge in the original hits. The efficacy of each scaffold against multiple species of Leishmania
and against drug resistant field isolates will be tested at an early stage to ascertain the potential of each
scaffold for applicability against a broad range of parasites causing distinct types of leishmaniasis and with or
without pre-established resistance to other currently employed, albeit non-optimal, antileishmanial drugs. The
rate of development of resistance will be monitored to ensure that leads that are pursued will be reasonably
stable against emergence of resistance during use in the field. In association with an extensive medicinal
chemistry program, in vivo pharmacokinetics and acute toxicity studies and ability to control visceral infections
in mice and hamsters will be determined to arrive at the top synthetic leads originating from the original 3 hits.
The overall objective is to develop several leads with highly promising characteristics for ultimate development
of desperately needed novel and effective drugs against this widespread and poorly controlled parasitic
disease.
Status | Finished |
---|---|
Effective start/end date | 12/14/16 → 11/30/18 |
Funding
- Oregon Health and Sciences University: $150,500.00
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