A wide variety of agents have been reported as 5-LO inhibitors. The majority of the series appear to be lipophilic reducing agents, including phenols, partially saturated aromatics, and compounds containing heteroatom-heteroatom bonds. Many of these are not selective 5-LO inhibitors, but often affect CO and other LOs as well. In vivo systemic activity for many of these has been, in general, disappointing, probably because of poor bioavailability caused by lipophilicity and metabolic instability (oxidation, and conjugation of phenolic compounds). However, topically a number of agents have shown promise for skin inflammation, with Syntex's lonapalene the most advanced of these. Most results published to date appear more disappointing in the allergy/asthma field. More excitingly, a few structural types are selective 5-LO inhibitors which have shown systemic activity in vivo and in the clinic. Abbott's zileuton (136) appears to be one of the leading compounds in this category, along with other hydroxamates such as BW-A4C (129) from Burroughs-Wellcome. Recent selective non-reducing agents such as Wyeth-Ayerst's Wy-50,295 (143) and the similar ICI compounds such as ICI 216800 (145) also hold promise. The enantiospecific effects of (106) and (145) are especially interesting for the design of new inhibitors. If compounds like these validate the hypothesis that inhibition of 5-LO will have a significant anti-inflammatory effect, a redoubling of effort throughout the industry to find second- and third-generation selective agents may be expected. Part of the difficulty in interpreting and comparing the 5-LO literature is the plethora of test methods and activity criteria. As pointed out in the introduction, inhibition of product release from cells, often stimulated with A23187, has commonly been used to demonstrate 5-LO inhibition. However, this type of assay cannot be assumed to be diagnostic for 5-LO inhibition. Only if specificity for 5-LO product generation and (ideally) activity in cell-free enzymes is also shown should mechanistic interpretations be made. Recently, a new class of compounds was found at Merck which inhibited LT biosynthesis without inhibiting 5-LO, but apparently by a novel, specific mechanism. L-655,240 (169) and L-663,536 (MK-886) (170) were both active in human ISN, with IC50 values in the low micromolar range. Both also orally inhibited GPB (< 1 mg/kg). MK-886 was effective in Ascaris-induced asthma in squirrel monkeys, in rat carrageenan pleurisy, in rat Arthus pleurisy, and (topically) in guinea-pig ear oedema induced by A23187.(ABSTRACT TRUNCATED AT 400 WORDS)