Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase

Leukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl
leukotriene
C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that
drive type 2 inflammation, bronchoconstriction, and itch. Thus, LTC4S
represents an attractive drug target for the treatment of allergic
inflammatory diseases, but to date, no LTC4S inhibitor has been tested
in patients. Herein, we disclose the discovery and preclinical profiling
of the highly selective, oral LTC4S inhibitor GJG057 (compound 1), which exhibits 20-fold improved potency (IC50 = 44 nM) versus clinical candidate AZD9898 (IC50 = 900
nM) in a human whole blood LTC4 release assay. GJG057 showed efficacy
in a murine asthma exacerbation model as well as in a mastoparan-induced
skin challenge PK/PD model and was profiled in GLP toxicology studies.
Despite its promising properties, GJG057 was not progressed into clinical
trials as an oral drug. Its potential as a topical drug is currently
being evaluated.