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

Autor: Junya Shirai, Yoshiyuki Fukase, Tetsuji Kawamoto, Mitsunori Kono, Tsuneo Oda, Mikio Shirasaki, Yasushi Fujitani, Hiroyuki Watanabe, Hideyuki Nakagawa, Keiko Uga, Michiko Tawada, Naohiro Taya, Akira Shibata, Takashi Imada, Yoshihide Tomata, Masashi Yamasaki, Tomoya Yukawa, Shoji Fukumoto, Hidekazu Tokuhara, Satoshi Yamamoto, Naoki Ishii, Atsuko Ochida, Yoshihiro Banno
Rok vydání: 2018
Předmět:
Male
Models
Molecular
0301 basic medicine
Injections
Intradermal
Stereochemistry
Carboxylic acid
Clinical Biochemistry
Retinoic acid
Administration
Oral
Pharmaceutical Science
Crystallography
X-Ray
Interleukin-23
01 natural sciences
Biochemistry
Jurkat Cells
Mice
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
RAR-related orphan receptor gamma
Tetrahydroisoquinolines
Drug Discovery
Animals
Humans
Inverse agonist
Carboxylate
Molecular Biology
chemistry.chemical_classification
Mice
Inbred BALB C
Dose-Response Relationship
Drug
Molecular Structure
Bicyclic molecule
010405 organic chemistry
Tetrahydroisoquinoline
Organic Chemistry
Nuclear Receptor Subfamily 1
Group F
Member 3
0104 chemical sciences
030104 developmental biology
chemistry
Models
Animal
Cytokines
Molecular Medicine
Derivative (chemistry)
Zdroj: Bioorganic & Medicinal Chemistry. 26:470-482
ISSN: 0968-0896
DOI: 10.1016/j.bmc.2017.12.008
Popis: 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.
Databáze: OpenAIRE
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