title: Synthesis and Biological Evaluation of New Triazolo- and Imidazolopyridine RORγt Inverse Agonists.
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.
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Hintermann
authors.affiliation: ATI, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Guntermann
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Henri
authors.initials: H
authors.lastname: Mattes
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: David A
authors.initials: DA
authors.lastname: Carcache
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Juergen
authors.initials: J
authors.lastname: Wagner
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Vulpetti
authors.affiliation: ATI, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Billich
authors.affiliation: ATI, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Janet
authors.initials: J
authors.lastname: Dawson
authors.affiliation: ATI, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
authors.affiliation: CPC, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Kallen
authors.affiliation: MAP, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: Rowan
authors.initials: R
authors.lastname: Stringer
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.
authors.forename: David
authors.identifier: 0000-0002-7546-8674
authors.initials: D
authors.lastname: Orain
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D054314:Drug Inverse Agonism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D020381:Interleukin-17 / Q000097:blood; D015394:Molecular Structure; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011725:Pyridines; D018168:Receptors, Retinoic Acid; D014230:Triazoles
keywords: RORγt; imidazopyridines; inverse agonists; oxadiazoles; plasma protein binding