5M96

Synthesis and biological evaluation of new triazolo and imidazolopyridine RORgt inverse agonists

Summary for 5M96

• Entry DOI: 10.2210/pdb5m96/pdb
• Descriptor: Nuclear receptor ROR-gamma, ~{N}-[8-[[(3~{S})-4-cyclopentylcarbonyl-3-methyl-piperazin-1-yl]methyl]-7-methyl-imidazo[1,2-a]pyridin-6-yl]-2-methyl-pyrimidine-5-carboxamide (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: 2
• Total formula weight: 55510.23

Authors

Kallen, J. (deposition date: 2016-10-31, release date: 2016-12-14, Last modification date: 2024-05-08)

Primary citation

Hintermann, S.,Guntermann, C.,Mattes, H.,Carcache, D.A.,Wagner, J.,Vulpetti, A.,Billich, A.,Dawson, J.,Kaupmann, K.,Kallen, J.,Stringer, R.,Orain, D.
Synthesis and Biological Evaluation of New Triazolo- and Imidazolopyridine ROR gamma t Inverse Agonists.
ChemMedChem, 11:2640-2648, 2016

PubMed Abstract: Retinoic-acid-related orphan receptor γt (RORγt) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORγt inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORγt inverse agonists was designed. In addition, replacement of the terminal cyclopentylamide metabolic soft spot by five-membered heterocycles was investigated. From our efforts, we identified an optimal 6,7,8-substituted imidazo[1,2-a]pyridine core system and a 5-tert-butyl-1,2,4-oxadiazole as cyclopentylamide replacement leading to compounds 10 ((S)-N-(8-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide) and 33 ((S)-N-(8-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-3-methylpiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide). Both derivatives showed good pharmacological potencies in biochemical and cell-based assays combined with excellent physicochemical properties, including low to medium plasma protein binding across species. Finally, 10 and 33 were shown to be active in a rodent pharmacokinetic/pharmacodynamic (PK/PD) model after oral gavage at 15 mg kg , lowering IL-17 cytokine production in ex vivo antigen recall assays.

PubMed: 27902884
DOI: 10.1002/cmdc.201600500

Experimental method

X-RAY DIFFRACTION (1.77 Å)