Structure-Guided Elaboration of a Fragment-Like Hit into an Orally Efficacious Leukotriene A4 Hydrolase Inhibitor

Leukotriene A4 hydrolase (LTA4H) is the final and rate-limiting
enzyme in the biosynthesis of pro-inflammatory leukotriene B4 (LTB4). Preclinical studies have provided strong evidence that
LTA4H is an attractive drug target for the treatment of chronic inflammatory
diseases. Here, we describe the transformation of compound 2, a fragment-like hit, into the potent inhibitor of LTA4H 3. Our strategy involved two key steps. First, we aimed to increase
the polarity of fragment 2 to improve its drug-likeness,
particularly its solubility, while preserving both its promising potency
and low molecular weight. Second, we utilized structural information
and incorporated a basic amino function, which allowed for the formation
of an essential hydrogen bond with Q136 of LTA4H and consequently
enhanced the potency. Compound 3 exhibited exceptional
selectivity and showed oral efficacy in a KRN passive serum-induced
arthritis model in mice. The anticipated human dose to achieve 90%
target engagement at the trough concentration was determined to be
40 mg administered once daily.