Hoegenauer, Klemens, Kallen, Joerg, Jimenez-Nunez, Eloisa, Strang, Ross, Ertl, Peter, Cooke, Nigel Graham, Hintermann, Samuel, Voegtle, Markus, Betschart, Claudia, McKay, Daniel, Wagner, Juergen, Ottl, Johannes, Beerli, Christian, Billich, Andreas, Dawson King, Janet, Kaupmann, Klemens, Streiff, Markus, Gobeau, Nathalie, Harlfinger, Stephanie, Stringer, Rowan and Guntermann, Christine (2019) Structure-based and property-driven optimization of N-aryl imidazoles towards potent and selective oral RORγt inhibitors. Journal of medicinal chemistry, 62 (23). pp. 10816-10832. ISSN 1520-4804; 0022-2623

Abstract

RORγt is considered the master transcription factor for the development of Th17 cells that produce pro-inflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput FRET screen, we identified compound 1 as hit with promising lipE. Using structure-based drug design based on a number of X-ray co-crystal structures, we morphed this hit class into potent imidazoles, exemplified by compound 3. To improve the poor ADME properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents towards a polar, water rich area of the protein. This highly lipophilicity efficient modification ultimately led to the discovery of compound 14, a potent and selective inhibitor of RORγt with good ADME properties and excellent in vivo pharmacokinetics. This compound showed good efficacy in an in vivo delayed-type hypersensitivity pharmacology model in rats.

Item Type:	Article
Date Deposited:	18 Jan 2020 00:45
Last Modified:	18 Jan 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41560