The development of novel LTA4H modulators to selectively target LTB4 generation

Abstract

The pro-inflammatory mediator leukotriene B4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4 hydrolase (LTA4H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4 generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic.

Feasibility and physiological relevance of designing highly potent aminopeptidase-sparing leukotriene A4 hydrolase inhibitors

“…However, similar to what was reported recently by Low et al . 15 , these compounds turned out to inhibit both activities of the enzyme and were not epoxide hydrolase selective. Indeed, we found that close and even smaller analogues of ARM1 and 4-MDM also failed to show any selectivity for the epoxide hydrolase function of the enzyme (Table 1 ).…”

“…Recent reports, however, have described small fragments that utilize almost exclusively the hydrophobic LTA4 binding site. These fragments were claimed not to interfere with PGP degradation or to even augment the peptidase activity of the enzyme 12 – 15 .…”

Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis

“…Encouragingly, this resulted in a modest reduction in CF exacerbations in a recent phase IIb trial. It could be argued that Acebilustat would inadvertently lead to PGP accumulation, which in turn could mask some of the benefits of ameliorating LTB 4 -driven inflammation [ 41 ]. However, our current study demonstrates that PGP degradation by LTA 4 H is already aberrant in CC-CF children, potentially owing to degradation of LTA 4 H by neutrophil elastase, and thus it is feasible that any potential adverse effects of Acebilustat in inhibiting PGP degradation by LTA 4 H would be negligible in CF.…”

Leukotriene A4hydrolase deficiency protects mice from diet‐induced obesity by increasing energy expenditure through neuroendocrine axis

“…Third, experiments aimed at determining the roles of the aminopeptidase activity of LTA 4 H in obesity would be of great interest. LTA 4 H inhibitors are currently being developed, [35][36][37] and LTA 4 H inhibition might increase HFDinduced thermogenesis, which would make it a promising therapeutic target for obesity.…”