6Q6M
RORCVAR2 (RORGT, 264-499) IN COMPLEX WITH COMPOUND 1: Identification of N-aryl imidazoles as potent and selective RORgt inhibitors
Summary for 6Q6M
| Entry DOI | 10.2210/pdb6q6m/pdb |
| Descriptor | Nuclear receptor ROR-gamma, ethyl (2~{S})-2-[(2-chloranyl-6-methyl-phenyl)-thiophen-2-ylcarbonyl-amino]propanoate (3 entities in total) |
| Functional Keywords | nuclear hormone receptor, ligand-binding domain, inverse agonist, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 27981.79 |
| Authors | Kallen, J. (deposition date: 2018-12-11, release date: 2019-11-27, Last modification date: 2024-01-24) |
| Primary citation | Hoegenauer, K.,Kallen, J.,Jimenez-Nunez, E.,Strang, R.,Ertl, P.,Cooke, N.G.,Hintermann, S.,Voegtle, M.,Betschart, C.,McKay, D.J.J.,Wagner, J.,Ottl, J.,Beerli, C.,Billich, A.,Dawson, J.,Kaupmann, K.,Streiff, M.,Gobeau, N.,Harlfinger, S.,Stringer, R.,Guntermann, C. Structure-Based and Property-Driven Optimization ofN-Aryl Imidazoles toward Potent and Selective Oral ROR gamma t Inhibitors. J.Med.Chem., 62:10816-10832, 2019 Cited by PubMed Abstract: Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is considered to be the master transcription factor for the development of Th17 cells that produce proinflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput fluorescence resonance energy transfer (FRET) screen, we identified compound 1 as a hit with promising lipophilic efficiency (LipE). Using structure-based drug design based on a number of X-ray cocrystal structures, we morphed this hit class into potent imidazoles, exemplified by compound . To improve the poor absorption, distribution, metabolism, and excretion (ADME) properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents toward a polar, water-rich area of the protein. This highly lipophilicity-efficient modification ultimately led to the discovery of compound , 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. PubMed: 31729873DOI: 10.1021/acs.jmedchem.9b01291 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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