학술논문
Discovery of [cis-3-({(5R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor ?t Inverse Agonist.
Document Type
Article
Author
Mitsunori Kono; Atsuko Ochida; Tsuneo Oda; Takashi Imada; Yoshihiro Banno; Naohiro Taya; Shinichi Masada; Tetsuji Kawamoto; Kazuko Yonemori; Yoshi Nara; Yoshiyuki Fukase; Tomoya Yukawa; Hidekazu Tokuhara; Skene, Robert; Bi-Ching Sang; Hoffman, Isaac D.; Snell, Gyorgy P.; Keiko Uga; Akira Shibata; Keiko Igaki
Source
Subject
*ACETIC acid
*TRETINOIN
*ORAL drug administration
*ORGANIC synthesis
*DRUG design
*TETRAHYDROISOQUINOLINES
*DRUG lipophilicity
*THERAPEUTICS
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Language
ISSN
0022-2623
Abstract
A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [cis-3-({(5R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases. [ABSTRACT FROM AUTHOR]