R-Praziquantel

Praziquantel (PZQ) is the most effective treatment for schistosomiasis, commonly administered as a racemic mixture of the two enantiomers. Despite many reports on the pharmacokinetics of PZQ, the stereoselective pharmacokinetics of PZQ and its major metabolite 4‐hydroxypraziquantel (4‐OH‐PZQ) remain poorly understood in goats. In this study, the chiral LC‐MS/MS method was further optimized for separating and quantifying PZQ, trans‐4‐OH‐PZQ, and cis‐4‐OH‐PZQ and their enantiomers and then applied for the molecular pharmacokinetics of three analytes in black goat plasma. The findings showed that PZQ was rapidly absorbed and metabolized to 4‐OH‐PZQ. The Cmax of trans‐4‐OH‐PZQ was about 3 times and 6 times higher than those of cis‐4‐OH‐PZQ and PZQ, respectively. The stereoselectivity of the PZQ and cis‐4‐OH‐PZQ enantiomers was insignificant in black goat plasma (p > 0.05), whereas the trans‐4‐OH‐PZQ enantiomers exhibited obvious stereoselectivity (p < 0.05). The Cmax of S‐trans‐4‐OH‐PZQ were ~3.1 times higher than that of R‐trans‐4‐OH‐PZQ. Further computer simulations indicated that these differences in the stereoselectivity might mainly stem from the different binding energies of the corresponding R‐ and S‐enantiomers of the target analytes to black goat plasma albumin. It has guiding significance for the research on the stereoselectivity of chiral veterinary drugs and their precision medication.

Growing interest in improved structural diversity within the pharmaceutical industry has led to a focus on more sp3‐rich drug frameworks. Meanwhile, spiralling pharmaceutical research and development costs continue to require expedited adsorption, distribution, metabolism, excretion, and toxicity studies, which are heavily reliant on the use of molecules incorporating deuterium and tritium. Herein, we report an iridium catalyzed C(sp3)−H activation and hydrogen isotope exchange (HIE) methodology capable of utilizing pharmaceutically ubiquitous nitrogen‐based carbonyl directing groups. High levels of deuterium incorporation (>80% in 37 of the examples) are demonstrated across a range of substrates (5‐, 6‐, and 7‐membered lactams, cyclic carbamates and ureas, acyclic amides), with tolerance of a range of common functional groups (aryl, alkoxy, halogen, ester, alcohol, sulfonamide) and predictable regioselectivity. The applicability of this methodology was demonstrated with up to 98% deuterium incorporation observed in a range of challenging bioactive molecules such as Nefiracetam, Praziquantel, and Unifiram. Density functional theory has provided mechanistic insight into the C−H activation and HIE at both the expected site of incorporation and an unexpected aryl labelling via a 7‐membered metallocyclic intermediate.