A new series of potential human 5-LOX inhibitors structurally related to the 1-phenyl-3-pyrazolidinone (phenidone, 2) has been synthesized and the activity against COX-1, COX-2, and human 5-LOX enzymes has been evaluated. In contrast with literature data, we observed that phenidone resulted to be inactive against human 5-LOX, while retains its activity against cyclooxygenases in a micromolar range. The present results suggest that the substitution of the amino function at the 4-position is detrimental in terms of activity toward COX-1 and COX-2, while the presence of a double bond at the 4,5-position does not alter the biological profile against COX. The absence of activity vs. human 5-LOX strongly suggests a re-consideration of phenidone and its analogs as 5-LOX inhibitors in humans.