Discovery of orally efficacious RORγt inverse agonists, Part 1: Identification of novel phenylglycinamides as lead scaffolds

Publication date: Available online 9 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Junya Shirai, Yoshihide Tomata, Mitsunori Kono, Atsuko Ochida, Yoshiyuki Fukase, Ayumu Sato, Shinichi Masada, Tetsuji Kawamoto, Kazuko Yonemori, Ryoukichi Koyama, Hideyuki Nakagawa, Masaharu Nakayama, Keiko Uga, Akira Shibata, Keiko Koga, Toshitake Okui, Mikio Shirasaki, Robert Skene, BiChing Sang, Isaac Hoffman, Wes Lane, Yasushi Fujitani, Masashi Yamasaki, Satoshi Yamamoto
A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.

Graphical abstract

http://ift.tt/2BAoQSy