The development of novel LTA₄H modulators to selectively target LTB₄ generation

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.