Deuterated Analogs of Praziquantel for Treatment of Schistosomiasis

血吸虫病由寄生血吸虫引起，是一种被忽视的热带病，需要进一步研究和治疗。血吸虫病是仅次于疟疾的最具破坏性的寄生虫病，在非洲、南美洲、加勒比地区、中东、中国南部以及东南亚部分地区、老挝和菲律宾，全世界有2亿多人受到感染。目前血吸虫病的护理标准是口服吡喹酮（PZQ）治疗。

Schistosomiasis, or bilharzia, is caused by parasitic schistosoma worms and is a neglected tropical disease in need of further research and treatment efforts. Schistosomiasis is second only to malaria as the most devastating parasitic disease, and more than 200 million people are infected worldwide in Africa, South America, the Caribbean, the Middle East, southern China and parts of Southeast Asia, Laos and the Philippines. The current standard of care for schistosomiasis is treatment with oral praziquantel (PZQ). PZQ is well absorbed (80 percent) but is highly metabolized via a pronounced first-pass effect, resulting in low effective bio-availability. Over 99 percent of the dose is converted to oxidative metabolites via liver enzymes. As a result, to achieve therapeutic blood levels, patients must be dosed repeatedly with multiple 600-mg tablets of PZQ at a level of 40-60 mg/kg over one to two days. PZQ is dosed as a racemate (50:50 mixture of R- and S-enantiomers), but only the R-enantiomer contributes to the anti-parasitic efficacy. PZQ has an extremely bitter taste that can lead to vomiting. Interestingly, the bitter taste is more associated with the unneeded S-enantiomer than with the active R-enantiomer. CoNCERT Pharmaceuticals synthesized deuterated analogs of PZQ and has demonstrated that selective deuterium incorporation imparts significant metabolic stabilization in vitro. Additionally, the company has prepared R-enantiomers of its analogs, which may further facilitate smaller pill sizes, fewer pills per dose and a more palatable taste profile through the elimination of the unneeded S-enantiomer. After studying the metabolic stability of modified forms of PZQ, TRND selected a PZQ analog for further development. These studies included identification of PZQ metabolites, and efficacy studies in cells and animal models. During conduct of this research, Merck KGaA, as part of the Pediatric Praziquantel Consortium, announced a commitment to develop formulations of PZQ. In light of this announcement, TRND concluded that the medical need for developing modified forms of PZQ to treat schistosomiasis has been met.