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

Hintermann, Samuel, Guntermann, Christine, Mattes, Henri, Carcache, David, Vulpetti, Anna, Dawson King, Janet, Kaupmann, Klemens, Kallen, Joerg, Stringer, Rowan, Orain, David, Wagner, Juergen and Billich, Andreas (2016) Synthesis and biological evaluation of new triazolo and imidazolopyridine RORγt inverse agonists. ChemMedChem : chemistry enabling drug discovery, 11 (24). pp. 2640-2678. ISSN 1860-7179


RORγt is a key transcription factor implicated in the release of pro-inflammatory Th17 cytokines which drive a number of autoimmune diseases. Despite many chemical series reported in the literature, combining high potency and a good physicochemical profile has been a very challenging task in the RORC inhibitor field. Based on available structures and incorporating in-house knowledge, a new series of triazolo and imidazopyridine RORγt inverse agonists was designed. In addition, modulation of a terminal cyclopentylamide metabolic soft spot by 5-membered heterocycles was investigated. From our efforts we have identified an optimal 6,7,8-substituted imidazo[1,2-a]pyridine core system and a 5-tertbutyl 1,2,4-oxadiazole as cyclopentylamide replacement leading to 10 and 33. Both derivatives showed good pharmacological potencies in biochemical and cell 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 PK/PD model after oral gavage at 15 mg/kg lowering IL-17 concentrations in ex-vivo recall assays experiments.

Item Type: Article
Keywords: English
Date Deposited: 03 Jan 2017 00:45
Last Modified: 03 Jan 2017 00:45


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