Graduation Date

Summer 8-14-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dr. Jonathan L. Vennerstrom

Second Advisor

Dr. James P. Hagen

Third Advisor

Dr. Haizhen Zhong

Fourth Advisor

Dr. Yuxiang Dong

Abstract

Schistosomiasis, also known as “snail fever,” is both an acute and chronic disease spread by trematode flukes from the tropical parasitic worm genus Schistosoma. The flukes are spread via diseased freshwater snails, which release the parasites into the water column where they find a new human host. According to the World Health Organization (WHO), 99 million people were treated for schistosomiasis in 2017. The primary treatment used to combat schistosomiasis is the drug praziquantel (PZQ), but due to high drug pressure and widespread administration, its effectiveness has eroded because of rising drug resistance. Furthermore, PZQ is active against adult but not juvenile schistosomes, a potential factor regarding the frequently observed failed treatments.

In 1980, the orally active hydantoin Ro 13-3978 was identified as a compound with antischistosomal activity. Although Ro 13-3978 is an effective inhibitor of schistosome growth, its antiandrogenic side effects on the host were undesirable. Utilizing the Ro 13-3978 scaffold as a starting point, we developed several libraries of structurally diverse analogs of Ro 13-3978. While numerous compounds identified exhibited good antischistosomal activity and lower antiandrogenic effects compared to Ro 13-3978, the desired potency was not achieved and a clear correlation between good activity/low side effects and compound structural features was indistinct. Building on this foundation, we reexamined the Ro 13-3978 SAR and designed a series of compounds to strategically separate the desired antischistosomal properties of aryl hydantoins from the undesirable antiandrogenic side effects.

This research translated to the discovery of drug candidate 27 (AR102), which like Ro 13-3978, has high adult in vivo antischistosomal activity, but unlike Ro 13-3978, has substantial juvenile in vivo antischistosomal activity and no androgen receptor activity. Drug candidate 27 also possesses superior pharmacokinetic properties compared to Ro 13-3978. After scale-up synthesis, 27 is now progressing up the drug discovery ladder and we anticipate it will function as a new potent schistosomiasis treatment with broad-spectrum activity against multiple schistosome species and life stages.

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