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

Abstract

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 multi-dose 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 hours 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.

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Following the discovery of diphenyl ether containing pyridones (e.g., 621 , GW8445520) by Yeates et al., which were found to inhibit the cytochrome bc 1 complex of Plasmodium , Riscoe and co‐workers developed further ELQ analogues including ELQ‐300 ( 622 ) as metabolically stable orally bioavailable antimalarial agents . Prodrugged analogues of 622 have further assisted in enhancing physicochemical and pharmacokinetic parameters for single‐dose curative agents . Similarly, ELQ‐316 ( 623 ) has been shown to effectively inhibit the Q i subunit of cytochrome b in T. gondii .…”

Microbial esterases and ester prodrugs: An unlikely marriage for combating antibiotic resistance

“…In a recent follow‐up publication, the carbonate ester was replaced with an alkoxycarbonate ester, a promoiety found in some FDA‐approved prodrugs (Bodin et al, ). This new analog, ELQ‐331, was synthesized in a single step from ELQ‐300 and showed an even lower degree of crystallinity and high performance in both in vitro and in vivo models (Figure d; Frueh et al, ). In particular, ELQ‐331 showed evidence of being cleaved by parasitic esterases in addition to host esterases, suggesting that the alkoxycarbonate moiety may further improve target specificity.…”

“…Esterase activation opens the 7-membered lactone ring, freeing the alkyne functionality to undergo Diels-Alder cycloaddition with the cyclopentadienone core. The intermediate rearranges to release CO and the final cyclization product and high performance in both in vitro and in vivo models (Figure 4d; Frueh et al, 2017). In particular, ELQ-331 showed evidence of being cleaved by parasitic esterases in addition to host esterases, suggesting that the alkoxycarbonate moiety may further improve target specificity.…”

ELQ-331 as a prototype for extremely durable chemoprotection against malaria

“…It acts at the Qi site of cytochrome bc1 to selectively inhibit parasite mitochondrial electron transport and inter-related pyrimidine biosynthesis (17,18), thus preventing nucleic acid synthesis. ELQ-300 has low nanomolar efficacy in vitro against (17,19). ELQ-494, ELQ-495, ELQ-499, and ELQ-500 will be described as part of a future report covering the entire scope of the ELQ-300 prodrug project.…”

“…To improve oral bioavailability while preserving the highly desirable features of ELQ-300, we have sought to develop prodrugs of ELQ-300 that are better absorbed from the gastrointestinal tract but then are rapidly converted to ELQ-300 (19,22). ELQ-331 (see Table 1), an alkoxycarbonate ester of ELQ-300, has emerged as a leading contender.…”