Pharmacokinetics and Safety of Z‐321, a Novel Specific Orally Active Prolyl Endopeptidase Inhibitor, in Healthy Male Volunteers

Abstract

This study investigates the pharmacokinetics and safety profile of Z‐321, (4R)‐3‐(indan‐2‐ylacetyl)‐4‐(1‐pyrrolidinylcarbonyl)‐1,3‐thiazolidine, a novel specific orally active prolyl endopeptidase (PEP) inhibitor. Following a preliminary safety evaluation wherein 2 subjects received 3.75 and 15 mg doses and 2 other subjects received 7.5 and 30 mg doses, 16 subjects were assigned to two groups of 8 subjects each. In each group, 6 subjects were to receive active treatment, and 1 or 2 subjects were to receive placebo treatment. One group received 60 mg under fasted and fed conditions. A separate group of 8 subjects received 60 mg of Z‐321 or a placebo in a bid regimen for 6 days and the morning dose on day 7. The concentrations of Z‐321 and its main metabolites—R‐ and S‐sulfoxide; RR‐, SS‐, and RS‐indanol; and indanolsulfoxides in plasma and urine—were determined by the HPLC method. In the multiple‐dose study, the cholinesterase activity was gradually increased and reached above the normal range on day 8 in 3 of 6 subjects given Z‐321 and gradually returned to the normal range after completion of dosing. The elevation of plasma cholinesterase activity was considered to be an action of Z‐321, but this remains to be verified. In a single‐dose study at a dose of 30 mg, headache and vomiting were observed in 1 of 6 subjects. In the multiple‐dose study, slight skin itching and eczema in 3 and 2 of 6 subjects, respectively, and headache in 2 of 6 subjects were observed, but all symptoms were not severe. There were no other abnormal findings in objective signs and laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, and urinalysis. The Cmax of Z‐321 at 30, 60, and 120 mg in the fasting state were 63.7 ± 23.9, 102.0 ± 43.1, and 543.3 ± 437.0 ng/ml (mean ± SD), respectively, at 0.9 hours after administration, and the t1/2 was about 1.8 hours. There were no dramatic changes in the pharmacokinetics of Z‐321 in the presence of food. In the multiple‐dose study, there was no drug accumulation trend in plasma. These results indicate that Z‐321 has acceptable pharmacodynamic and pharmacokinetics profiles for clinical use without any serious adverse events, as verified in healthy young male volunteers.

A prolyl oligopeptidase inhibitor reduces tau pathology in cellular models and in mice with tauopathy

“…Prolyl oligopeptidase inhibition produced disease-modifying effects by activating PP2A, consequently reducing tau phosphorylation, enhancing autophagy, and reducing oxidative stress; thus, i.e., it provided a multitarget approach to tackle tau-dependent toxicity in the PS19 mice. Furthermore, neither toxicity nor serious adverse events have been reported in previous preclinical or clinical studies after prolyl oligopeptidase inhibition ( 75 – 77 ). Prolyl oligopeptidase inhibition could have potential as a disease-modifying treatment for tauopathies and maybe other neurodegenerative diseases characterized by multiple toxic mechanisms ( 78 ).…”

“…Prolyl oligopeptidase inhibition produced disease-modifying effects by activating PP2A, consequently reducing tau phosphorylation, enhancing autophagy, and reducing oxidative stress; thus, i.e., it provided a multitarget approach to tackle tau-dependent toxicity in the PS19 mice. Furthermore, neither toxicity nor serious adverse events have been reported in previous preclinical or clinical studies after prolyl oligopeptidase inhibition (75)(76)(77) A priori power analysis based on our behavioral characterization experiments was performed for the sample size estimation of PS19 transgenic mice needed in the treatment phase of the in vivo study. With an α = 0.05 and power (1 -β) = 0.9, the estimated sample size for four treatment groups was 71 to achieve a 0.5 effect size between the treatment groups (G*power, version 3.1.9.2.).…”

Nonpeptidic Oxazole-Based Prolyl Oligopeptidase Ligands with Disease-Modifying Effects on α-Synuclein Mouse Models of Parkinson’s Disease

“…The crude product was obtained as a yellow sap, which after flash chromatography (heptane/ EtOAc 17:3 → 1:4) yielded compound 15 as a yellow oil (87 mg, 20%). 1 (16). Synthesized according to method A using compound 47 (854 mg, 2.47 mmol).…”

“…The development of PREP ligands was originally focused on inhibiting proteolytic activity, and a few potent inhibitors entered clinical trials. − These trials did not advance, to our understanding, due to a lack of efficacy, but they showed that at least short-term PREP inhibition is safe in humans. Interestingly, the most recent compound that entered clinical trials, S17092, had no effect on the PPI-mediated functions of PREP when it was later evaluated in our assays .…”