Alzheimer's disease (AD) is the most common cause of dementia. Since no causative treatment is available, new therapeutic options are utmost needed. Several pirinixic acid derivatives, including MH84 (2-((4,6-bis(4-(trifluoromethyl)phenethoxy)pyrimidin-2-yl)thio)hexanoic acid), have shown promising in vitro results as γ-secretase modulators as well as PPARγ activators as potential pharmacological compounds against AD.
Using a newly developed and validated sensitive LC–MS (APCI-qTOF mass analyzer) method, the pharmacokinetic and long-term accumulating properties as well as the blood–brain-barrier permeability of MH84 were evaluated in a preclinical animal study. MH84 was administered to mice by oral gavage with a dose of 12 mg/kg. Nine time points from 0.5 to 48 h with 6 animals per point were investigated. Additionally 6 animals were fed daily, for 21 days with an identical dose to determine possible long-term accumulation in plasma and brain tissue.
The sample preparation was performed by a liquid-liquid extraction on Extrelut® columns whereas the LC separation was operated on a MulthoHigh 100 RP 18-5 μ column (125 × 4 mm) using an isocratic mobile phase of formic acid (0.1% (v/v))–methanol mixture (11:89 (v/v)) at a flow rate of 1 ml/min. The validation confirmed the new LC–MS method to be precise, accurate and reliable. After oral application, Cmax and Tmax of unmetabolized MH84 was determined to be 10.90 μg/ml and 3 h in plasma. In brain tissue a constant level of 300 to maximum 320.64 ng/g was found after 1.5–6 h. Daily gavage for 21 days did not lead to a long-term drug accumulation in the brain. The efficacy of the obtained MH84 levels needs to be investigated in further preclinical pharmacodynamic animal studies.