Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria

作者：Frueh Lisa; Li Yuexin; Mather Michael W; Li Qigui; Pou Sovitj; Nilsen Aaron; Winter Rolf W; Forquer Isaac P; Pershing April M; Xie Lisa H; Smilkstein Martin J; Caridha Diana; Koop Dennis R^*; Campbell Robert F; Sciotti Richard J; Kreishman Deitrick Mara; Kelly Jane X; Vesely Brian^*; Vaidya Akhil B^*; Riscoe Michael K^*

来源：ACS Infectious Diseases, 2017, 3(10): 728-735.

DOI：10.1021/acsinfecdis.7b00062

• malaria
• cytochrome bc1
• Plasmodium falciparum
• prodrug

ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. While ELQ-300 is highly effective when administered in a low multidose regimen, poor aqueous solubility and high crystallinity have hindered its clinical development. To overcome its challenging physiochemical properties, a number of bioreversible alkoxycarbonate ester prodrugs of ELQ-300 were synthesized. These bioreversible prodrugs are converted to ELQ-300 by host and parasite esterase action in the liver and bloodstream of the host. One such alkoxycarbonate prodrug, ELQ-331, is curative against Plasmodium yoelii with a single low dose of 3 mg/kg in a murine model of patent malaria infection. ELQ-331 is at least as fully protective as ELQ-300 in a murine malaria prophylaxis model when delivered 24 h before sporozoite inoculation at an oral dose of 1 mg/kg. Here, we show that ELQ-331 is a promising prodrug of ELQ-300 with improved physiochemical and metabolic properties and excellent potential for clinical formulation.

• 出版日期2017-10