The development of novel LTAH modulators to selectively target LTB generation.

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