- Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives
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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.
- Kono, Mitsunori,Oda, Tsuneo,Tawada, Michiko,Imada, Takashi,Banno, Yoshihiro,Taya, Naohiro,Kawamoto, Tetsuji,Tokuhara, Hidekazu,Tomata, Yoshihide,Ishii, Naoki,Ochida, Atsuko,Fukase, Yoshiyuki,Yukawa, Tomoya,Fukumoto, Shoji,Watanabe, Hiroyuki,Uga, Keiko,Shibata, Akira,Nakagawa, Hideyuki,Shirasaki, Mikio,Fujitani, Yasushi,Yamasaki, Masashi,Shirai, Junya,Yamamoto, Satoshi
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p. 470 - 482
(2018/01/05)
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- Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives
-
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.
- Kono, Mitsunori,Oda, Tsuneo,Tawada, Michiko,Imada, Takashi,Banno, Yoshihiro,Taya, Naohiro,Kawamoto, Tetsuji,Tokuhara, Hidekazu,Tomata, Yoshihide,Ishii, Naoki,Ochida, Atsuko,Fukase, Yoshiyuki,Yukawa, Tomoya,Fukumoto, Shoji,Watanabe, Hiroyuki,Uga, Keiko,Shibata, Akira,Nakagawa, Hideyuki,Shirasaki, Mikio,Fujitani, Yasushi,Yamasaki, Masashi,Shirai, Junya,Yamamoto, Satoshi
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p. 470 - 482
(2019/05/09)
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- Heterocyclic compound
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The present invention relates to compound (I) or a salt thereof which has a ROR γ t inhibitory action. wherein each symbol is as defined in the specification.
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- HETEROCYCLIC COMPOUNDS AND THEIR USE AS RETINOID-RELATED ORPHAN RECEPTOR (ROR) GAMMA-T INHIBITORS
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Provided are heterocyclic compounds having a RORγt inhibitory action represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.
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Paragraph 0310
(2016/01/25)
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- SUBSTITUTED TETRAHYDROISOQUINOLINE COMPOUNDS AS FACTOR XIA INHIBITORS
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The present invention provides compounds of Formula (I): or stereoisomers, pharmaceutically acceptable salts thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of factor XIa and/or plasma kallikrein which may be used as medicaments.
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- Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity
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Tetrahydroisoquinoline analogs are provided which are modulators of chemokine receptor activity. The tetrahdroisoquinoline analogs thereof have the structure wherein R1, R2, R3, R3a, X1, X2, X3, X4, m, n and p are as described herein.
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