生物活性

• 描述Fatty acid amides (FAA) are a diverse group of lipid mediators including arachidonoyl ethanolamide (AEA), oleoyl ethanolamide (OEA), palmitoyl ethanolamide (PEA) and N-arachidonoyl glycine. FAAs are hydrolyzed by several different enzymes with different substrate preferences. The metabolizing enzymes that hydrolyze FAA include fatty acid amide hydrolase (FAAH), and N-acylethanolamine-hydrolyzing acid amidase. JNJ-42165279 inhibits hFAAH and rFAAH with IC₅₀ of 70 ± 8 nM and 313 ± 28 nM respectively. In rats, JNJ-42165279 reached a maximum plasma concentration of 4.2 μM after 1 h, falling to about 130 nM at 8 h and declining to below the LLQ by 16 h. Observed concentrations in the brain were somewhat rised relative to plasma at the Cmax (6.3 μM at 1 h), but those differences diminished by the 8 h time-point (167 nM). In the multiple ascending dose (MAD) study, daily administration of JNJ-42165279 (10 mg, 25 mg, 75 mg) for 1 week increased the mean cerebrospinal fluid AEA and OEA concentrations by 45-77 fold and 6.6-7.4 fold, respectively, relative to predose values. Single doses of JNJ-42165279 in the range of 10-100 mg produced mean peak concentrations of AEA in plasma that were 5.5-10-fold higher than mean peak placebo values. ~10 mg of JNJ-42165279 resulted in saturation of brain FAAH occupancy.