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Synthesis and Biological Evaluation of New Triazolo- And Imidazolopyridine RORγt Inverse Agonists

Synthesis and Biological Evaluation of New Triazolo- And Imidazolopyridine RORγt Inverse Agonists

Samuel Hintermann, Christine Guntermann, Henri Mattes, David A Carcache, Juergen Wagner, Anna Vulpetti, Andreas Billich, Janet Dawson, Klemens Kaupmann, Joerg Kallen, Rowan Stringer, David Orain

ChemMedChem. 2016 Dec 16;11(24):2640-2648.

PMID: 27902884

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-1 , lowering IL-17 cytokine production in ex vivo antigen recall assays.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
LS7931286	7-Methylimidazo[1,2-a]pyridine-6-boronic acid			Price

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