Inhibitors of Leukotriene A4 (LTA4) Hydrolase as Potential Anti-Inflammatory Agents

Thomas D. Penning

Abstract

Leukotriene A4 (LTA4) hydrolase is a zinc-containing enzyme which stereospecifically catalyzes the hydrolysis of the epoxide LTA4 to the diol leukotriene B4 (LTB4). There is substantial evidence that LTB4 plays a significant role in the amplification of many inflammatory disease states. Therapeutic agents which selectively inhibit LTA4 hydrolase would block the formation of LTB4 and thus be potentially useful for the treatment of inflammation. Numerous inhibitors of LTA4 hydrolase have been reported over the past 15-20 years. Several early inhibitors were based on the structure of the natural substrate, LTA4. Later approaches utilized known inhibitors of related zinc-containing metalloproteinases and led to the identification of captopril, bestatin and kelatorphan as potent inhibitors of LTA4 hydrolase. This led to the design of a number of peptide and non-peptide analogs which contained potential zincchelating moieties, including thiols, hydroxamates and norstatines. A more recent series of non-peptidic, non-zinc chelating inhibitors of LTA4 hydrolase has been reported. This work led to the identification of several novel classes of analogs, including imidazopyridines, amidines and cyclic and acyclic amino acid derivatives, ultimately resulting in the identification of two potential clinical candidates SC-56938 and SC-57461A.