Deuterated Analogs of Praziquantel for Treatment of Schistosomiasis

血吸虫病是由寄生性血吸虫引起的，是一种被忽视的热带疾病，需要进一步的研究和治疗。血吸虫病是仅次于疟疾的最具破坏性的寄生虫病，全球有2亿多人在非洲、南美、加勒比海、中东、中国南部和东南亚部分地区、老挝和菲律宾感染。目前治疗血吸虫病的标准是口服吡喹酮(PZQ)。 PZQ吸收良好(80%)，但通过显著的首过效应而高度代谢，导致有效生物利用度较低。超过99%的剂量通过肝酶转化为氧化代谢物。因此，为了达到治疗水平，患者必须在一到两天内重复服用600毫克的PZQ片剂，剂量为40-60毫克/公斤。PZQ是一种外消旋体(R-和S对映体的混合物为50：50)，但只有R-对映体有抗寄生虫的作用。PZQ有一种极苦的味道，可能会导致呕吐。有趣的是，苦味更多地与不需要的S对映体有关，而不是与活性R-对映体有关。Concert制药公司合成了PZQ的氢化类似物，并已证明选择性地掺入氢在体外具有显著的代谢稳定性。此外，该公司还制备了其类似物的R-对映体，通过消除不需要的S-对映体，可能进一步促进更小的药丸尺寸、更少的每剂药丸和更可口的味道。 在研究了修饰形式的PZQ的代谢稳定性后，TRND选择了一种PZQ类似物进行进一步开发。这些研究包括对PZQ代谢物的鉴定，以及在细胞和动物模型中的疗效研究。在进行这项研究期间，默克KGaA作为儿科吡喹酮联盟的一部分，宣布了开发PZQ配方的承诺。鉴于这一宣布，TRND得出结论，开发改良形式的PZQ治疗血吸虫病的医学需求已经得到满足。

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.