5m96

Publication Abstract from PubMed

Retinoic-acid-related orphan receptor gammat (RORgammat) 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 RORgammat inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORgammat 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-methylimida zo[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.

Synthesis and Biological Evaluation of New Triazolo- and Imidazolopyridine RORgammat Inverse Agonists.,Hintermann S, Guntermann C, Mattes H, Carcache DA, Wagner J, Vulpetti A, Billich A, Dawson J, Kaupmann K, Kallen J, Stringer R, Orain D ChemMedChem. 2016 Nov 30. doi: 10.1002/cmdc.201600500. PMID:27902884^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.