Chagas disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi, mainly transmitted by insect vectors called triatominae. T. cruzi colonizes the heart, gastrointestinal tract, and nervous system, causing progressive inflammation, which can lead to chronic human cardiopathy and/or gastrointestinal dysfunction. T. cruzi infects around 8 million people worldwide, mostly in Latin America. More recently Chagas disease has expanded beyond tropical zones to become an emerging economic and health burden in the United States, Spain, and the UK. Chemotherapeutic options for Chagas disease are limited to benznidazole and nifurtimox, which are used during the acute phase but cause severe side effects. The efficacy of these drugs in the chronic stage is debated, and neither drug is approved by the FDA for use in the USA. Sterol 14α-demethylase (CYP51) is an important therapeutic target for fungal and parasitic infections due to its key role in the biosynthesis of ergosterol, an essential component of the cell membranes of these pathogenic organisms. For the discovery of novel anti-Chagas agents targeting T. cruzi CYP51, a screening hit, which possesses moderate potency (EC50 = 680 nM) and poor microsome stability (t1/2 = &lt;5 min) and selectivity (inhibition of human CYP enzymes &gt;90% at 1 μM), was optimized through structure-based drug design and structure activity relationship approaches. Significantly improved CYP51 inhibitors have been developed, with EC50 = &lt;1 nM (cell-based assay), t1/2 = &gt;30 min, &lt;30% inhibition of human CYP enzymes at 1 μM, and excellent in vivo PK properties. The optimized inhibitors also showed excellent in vivo efficacy vs. T. cruzi in a mouse model, when delivered orally (&gt;99.9% suppression of parasites at 25 mg/kg, b.i.d, PO, 4-day treatment). This efficacy is similar to that obtained by using the current drug, benznidazole (50 mg/kg). Furthermore, the optimized inhibitors did not show any toxicity during 21-day treatment; mice maintained their body weight perfectly in this study. Clinical blood chemistry from the 21-day toxicity study also showed no difference between control and treated mice.

Discovery of novel anti-chagas agents targeting T. cruzi CYP51

249th National Meeting (2015)

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