Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

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

Search