Advances in Chagas disease drug development: 2009-2010

Abstract

Purpose of review: The need for better drugs to treat patients with Chagas disease remains urgent. This review summarizes the advancements in drug development over the past 2 years.

Recent findings: Drug development efforts are almost exclusively occurring as preclinical research, although phase II studies for the antifungal drug, posaconazole, and a prodrug of ravuconazole are being planned. Several recent laboratory investigations demonstrate anti-Trypanosoma cruzi activity of novel small molecules in animal models. These include nonpeptidic cruzain inhibitors, novel inhibitors of the sterol 14α-demethylase enzyme, new compounds (arylimidamides) related to pentamidine, derivatives of nifurtimox, compounds using ruthenium complexes, and several natural products. The recent implementation of a high-throughput screen of more than 300 000 compounds against intracellular T. cruzi amastigotes done at the Broad Institute is an important development, yielding approximately 300 selective inhibitors, many of which may serve as leads for medicinal chemistry efforts.

Summary: Progress is slow, but recent advancements in both drug development and advocacy for research on neglected diseases are encouraging. Efforts to define a target product profile and to harmonize methodologies for testing drugs for Chagas disease are described herein.

Figure 1. Compounds with anti-T. cruzi activity in mice

#1, non-peptidic cruzain inhibitor; #2, tipifarnib analog; #3, non-azole 14α-demethylase inhibitor; #4, miltefosine; #5, DB766; #6, nifurtimox; and #7, nifurtimox analog.

Figure 2. Additional compounds with anti-T. cruzi activity

#8, natural product cubebin; #9, benznidazole; #10, posaconazole; and #11, ravuconazole.