Pharmacokinetics and Tissue Distribution Study for 2‐(2‐Fluorophenyl)‐5‐Phenyl‐7‐Alkoxy‐ [1,2,4]Triazole[1,5‐a]Pyrimidine Antiepileptic Compounds in Rats

The development of novel active molecules with a clear target has always been an urgent need for the treatment of epilepsy. Previously, we reported 2-(2-fluorophenyl)-5-phenyl-7-propyl-[1,2,4]triazolo[1,5-a]pyrimidine (10C) as a selective and positive modulator of GABAA receptors, which exhibited excellent antiepileptic activity in mice with an ED50 value of 8.51 mg/kg. However, the pharmacokinetics (PK) profiles of this compound remain unclear. In this study, 10C and four analogs (10A, 10B, 10D, and 10E) as well as deuterated 10C were synthesized with high efficiency under optimized reaction conditions, and deuterated 10C was employed as an internal standard. The concentrations of the five compounds in rat plasma and of 10C in tissue homogenate were assayed using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The results indicated that, compared to the other four analogs, 10C exhibited the highest drug concentration in rat plasma at the same dosage, which provides a good explanation for its superior antiepileptic activity compared to the other four analogs. Following intraperitoneal injection, 10C displayed favorable pharmacokinetic characteristics (F = 41%) and excellent brain penetration potency (B/P = 1.9). Overall, compound 10C is a promising lead for the research and development of new small-molecule therapeutics for epilepsy.