KYP‐2047 Penetrates Mouse Brain and Effectively Inhibits Mouse Prolyl Oligopeptidase

AbstractRecent studies have indicated that specific prolyl oligopeptidase (PREP) inhibitors can modulate inflammation, angiogenesis and neurodegeneration. As most diseases that may be potential targets for PREP inhibitors are being modelled in mice, it is essential to evaluate the pharmacological properties of investigative PREP inhibitors in mice. This study characterizes the single‐dose brain pharmacokinetics and PREP inhibitory action of a potent PREP inhibitor, KYP‐2047, in wild‐type C57 mice. KYP‐2047 penetrated into the mouse brain rapidly (tmax≤10 min.) and achieved pharmacologically active concentrations after a single dose of 15 or 50 μmol/kg i.p. The brain/blood AUC ratio was 0.050 and 0.039 after 15 and 50 μmol/kg i.p., respectively. KYP‐2047 produced efficient brain PREP inhibition at both doses; 15 μmol/kg blocked PREP activity fully for 30 min., and it took 12 hr for the activity to recover, whereas 50 μmol/kg inhibited brain PREP activity fully for 1 hr, and most, 84%, of the activity had been restored by 12 hr. Both doses completely blocked PREP activity in liver for at least 1 hr, and only about 25% the activity was recovered within 12 hr. The pharmacokinetics and inhibition kinetics of KYP‐2047 in mice were found to be similar as those previously reported in rats and indicate that KYP‐2047 would need to be administered twice per day to achieve continuous brain PREP inhibition in mice. In conclusion, KYP‐2047 is a suitable pharmacological tool with which to assess the effects of PREP inhibition in mice.