Development of Novel Therapeutics for Leishmaniasis

The goal of this project is to identify novel compounds for development into orally bioavailable drugs to treat leishmaniasis. In the R33 phase, the Guy lab will be primary responsible for carrying out medicinal chemistry as well as murine dose ranging and pharmacokinetic studies. Specifically, we are seeking to identify compounds with potent activity against intracellular amastigotes, the life cycle stage of the Leishmania parasites that cause disease, low toxicity against mammalian cells, high oral bioavailability, and desirable pharmacokinetic (PK) properties. Medicinal chemistry optimization (Design, synthesis, purification, and characterization) We are prioritizing the chloronitrobenzamides (compound 5) as our top chemotype for advancement due to its potency against L. mexicana, L. donovani, and T. brucei, its favorable SAR for additional medicinal chemistry, and the extensive favorable in vivo PK studies that have been done by the Guy laboratory. The arylquins (VMS-7-25) will be our second priority due to their favorable SAR and efficacy against all L. mexicana, L. donovani, and T. brucei. The isoflavones (compound 4) are the third priority. Initial synthetic efforts will seek to address the major liabilities of the chloronitrobenzamides, which are its poor aqueous solubility (0.3 ìM) and modest oral bioavailability (ca. 15%). Thus, the next round of synthesis will build a small set of analogs designed to improve solubility and decrease metabolic clearance in order to improve oral bioavailability and efficacy. Murine dose ranging and pharmacokinetic studies Initial PK studies will include IV and PO dose-ranging in mice to provide an initial capture of oral bioavailability and plasma exposure, in vivo stability, and the period of time that the compound’s plasma exposure remains above the in vitro EC50 concentration. Thus, these studies are of greater utility for determining the potential for drug development than in vitro ADME studies that were used to triage hit scaffolds. For the best compounds, destined for in vivo efficacy studies, we will carry out a repeat dose exploratory toxicology in mice, mirroring the targeted schedule and dose and including satellite PK/tox, full clinical chemistry and hematology workup at sacrifice, and necropsy including histopathology.