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Synthesis and Biological Evaluation of New Triazolo‐ and Imidazolopyridine RORγt Inverse Agonists
Author(s) -
Hintermann Samuel,
Guntermann Christine,
Mattes Henri,
Carcache David A.,
Wagner Juergen,
Vulpetti Anna,
Billich Andreas,
Dawson Janet,
Kaupmann Klemens,
Kallen Joerg,
Stringer Rowan,
Orain David
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600500
Subject(s) - rar related orphan receptor gamma , chemistry , potency , pharmacology , pharmacokinetics , orphan receptor , imidazopyridine , stereochemistry , biochemistry , in vitro , transcription factor , medicine , gene
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.