Thoma, Gebhard, Miltz, Wolfgang, Srinivas, Honnappa, Penno, Carlos, Kiffe, Michael, Gajewska, Monika, Klein, Kai, Evans, Amanda, Beerli, Christian and Roehn, Till (2024) Structure Guided Elaboration of a Fragment-Like Hit into an Orally Efficacious Leukotriene A4 Hydrolase Inhibitor. Journal of medicinal chemistry.

Abstract

We describe the transformation of compound 2, a fragment-like hit, into the potent inhibitor of leukotriene A4 hydrolase (LTA4H) 3. Our strategy involved two key steps. Firstly, we aimed to increase the polarity of the fragment 2 to improve its drug-likeness, particularly its solubility, while preserving both its promising potency and low molecular weight. Secondly, 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.

Item Type:	Article
Date Deposited:	02 Apr 2024 00:45
Last Modified:	02 Apr 2024 00:45
URI:	https://oak.novartis.com/id/eprint/53009