Figure 1. LTA₄H inhibitors to have entered the clinic are non-selective and inhibit PGP degradation in vitro and in vivo.

Schematic representation of the binding site of LTA₄H showing the relative positions occupied by LTA₄ (a) and PGP (b). (c) Proposed solution for a new compound that sits in the narrow arm occupied by the hydrophobic tail of LTA₄, (Site A) blocking its hydrolysis, but retaining ability to cleave the tripeptide PGP (Site B). The capacity of DG-051 to inhibit LTA₄H epoxide hydrolase (LTB₄ generation; (d)) and aminopeptidase activities (PGP degradation; (e)). Overlay of the X-ray structures of ligand-LTA₄H structures of (f) SC57461 (blue; 3U9W.pdb) and (g) DG-051 (pink; 3FH7.pdb) with that of the stable PGP analogue OBP-Pro (white, 4MS6.pdb). The protein surface is coloured by amino acid hydrophobicity from most hydrophobic (orange) to hydrophilic (blue) through white regions. (h) JNJ-40929837 (green) was docked into the protein with Autodock Vina. Mice were orally administered SC57461A (i and j) or JNJ-40929837 (k and l) and serum aminopeptidase activity (i and k) or absolute PGP concentrations (j and l) were determined. IC₅₀ curves were generated from 3 technical replicates at each concentration of test compound and at least 2 biological replicates. Data for in vivo studies (i–l) are representative of 2 experiments with 5 mice per group. Results depicted as mean ± SEM. *P < 0.05, **P < 0.01 using Mann–Whitney statistical test.