Deuterated Analogs of Praziquantel for Treatment of Schistosomiasis

血吸虫病或血吸虫病是由寄生的寄生虫引起的，是一种被忽视的热带疾病，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、加勒比海、中东、中国南部和东南亚部分地区、老挝和菲律宾，全世界有2亿多人感染。目前血吸虫病的治疗标准是口服吡喹酮（PZQ）。 PZQ吸收良好（80%），但通过明显的首过效应高度代谢，导致有效生物利用度低。超过99%的剂量通过肝酶转化为氧化代谢物。因此，为了达到治疗性血液水平，患者必须在一到两天内以40-60 mg/kg的水平重复给予多片600 mg PZQ片剂。PZQ作为外消旋体（R-和S-对映体的50：50混合物）给药，但只有R-对映体有助于抗寄生虫功效。PZQ有一种非常苦的味道，可能会导致呕吐。有趣的是，苦味与不需要的S-对映体的相关性大于与活性R-对映体的相关性。CoNCERT Pharmaceuticals合成了PZQ的氘代类似物，并证明了选择性氘掺入在体外赋予显著的代谢稳定性。此外，该公司还制备了其类似物的R-对映异构体，这可能进一步促进更小的药丸尺寸，每剂量更少的药丸和更可口的味道，通过消除不需要的S-对映异构体。 在研究了PZQ修饰形式的代谢稳定性后，TRND选择了PZQ类似物进行进一步开发。这些研究包括PZQ代谢物的鉴定，以及在细胞和动物模型中的功效研究。在进行这项研究期间，Merck KGaA作为儿科吡喹酮联盟的一部分，宣布致力于开发PZQ制剂。根据这一声明，TRND得出结论，开发PZQ修饰形式治疗血吸虫病的医疗需求已经得到满足。

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.