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


Journal of Medicinal Chemistry


Thoma, Gebhard, Wolfgang Miltz, Honnappa Srinivas, Carlos A. Penno, Michael Kiffe, Monika Gajewska, Kai Klein, Amanda Evans, Christian Beerli, and Till A. Röhn



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.

Keywords: Q1 2024

Go to journal

Get in Touch

We strive to provide the best for our customers, and we are always ready to help. Please let us know if you have a question for us.

Follow us