Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives

Publication date: Available online 11 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Mitsunori Kono, Tsuneo Oda, Michiko Tawada, Takashi Imada, Yoshihiro Banno, Naohiro Taya, Tetsuji Kawamoto, Hidekazu Tokuhara, Yoshihide Tomata, Naoki Ishii, Atsuko Ochida, Yoshiyuki Fukase, Tomoya Yukawa, Shoji Fukumoto, Hiroyuki Watanabe, Keiko Uga, Akira Shibata, Hideyuki Nakagawa, Mikio Shirasaki, Yasushi Fujitani, Masashi Yamasaki, Junya Shirai, Satoshi Yamamoto
A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.

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