In Vitro Stability and Pharmacokinetics of Novel Antileishmanial Compounds
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Date
2007-06
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The Ohio State University
Abstract
Leishmaniasis, a disease caused by protozoan parasites of the genus Leishmania, affects millions of people worldwide [6]. Without effective treatment, visceral leishmaniasis is associated with a near 100% fatality rate, whereas other forms can be severely debilitating [6]. Current treatments are not ideal because of toxicity, resistance, expense, and inconvenience [6].
Work to develop new drugs is underway at The Ohio State University and is led by Dr. Karl Werbovetz. Over the past few years Dr. Werbovetz and colleagues have generated a library of antiparasitic compounds known to specifically target Leishmania and trypanosome tubulin. In the first round of derivatization, several dinitroanilines were synthesized and evaluated in in vitro efficacy and stability and in vivo efficacy studies to identify key regions of the molecules for efficacy and metabolism. The most promising of these dinitroaniline compounds, GB-II-150, demonstrates an in vitro selectivity of two orders of magnitude for African trypanosomes over mammalian cell lines [7]. GB-II-150 was further evaluated in an in vivo metabolism study in rats [3] and found to be extensively metabolized with the major products resulting from N1 ring oxidation, N4 alkane oxidation, and N4 oxidation [4]. Although GB-II-150 had a half-life of 170 minutes with intravenous administration, it was determined to be highly unstable with zero oral bioavailability when given via oral gavage [3]. Based on the results of these studies, analogs have been prepared in effort to achieve greater metabolic stability while maintaining selective antiparasitic activity [4].
A second round of derivatization and synthesis yielded another family of dinitroanilines that were again evaluated in vivo and in vitro for efficacy. My work has tested the in vitro stability and metabolism of several of these second generation dinitroaniline compounds that have shown antiparasitic activity. The most promising compound from this second round, TG-II-36, was also tested in an in vivo stability study to determine its pharmacokinetic properties. As a follow-up, ongoing work is being conducted on BTB-06237, an analog of a group of diphenyl thioether compounds that have also shown antiparasitic activity. This highly hydrophobic compound has presented serious challenges at early stages of analytical method development preventing adequate in vitro stability characterization.
Advisor: James Dalton
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Keywords
leishmaniasis, dinitroaniline, diphenyl thioether, tubulin