Discovery of orally efficacious RORγt inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds. Issue 2 (15th January 2018)

• Record Type: Journal Article
• Authors: Shirai, Junya; Tomata, Yoshihide; Kono, Mitsunori; Ochida, Atsuko; Fukase, Yoshiyuki; Sato, Ayumu; Masada, Shinichi; Kawamoto, Tetsuji; Yonemori, Kazuko; Koyama, Ryoukichi; Nakagawa, Hideyuki; Nakayama, Masaharu; Uga, Keiko; Shibata, Akira; Koga, Keiko; Okui, Toshitake; Shirasaki, Mikio; Skene, Robert; Sang, BiChing; Hoffman, Isaac; Lane, Wes; Fujitani, Yasushi; Yamasaki, Masashi; Yamamoto, Satoshi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 2(2018)
• Page Start: 483
• Page End: 500
• Publication Date: 2018-01-15
• Subjects: Retinoic acid receptor-related orphan receptor-gamma t (RORγt) -- Inverse agonist -- Autoimmune disease -- Th17 -- IL-17 -- Phenylglycinamide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.12.006
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.