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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 γt Inverse Agonist

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posted on 06.03.2018, 00:00 by 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, Robert Skene, Bi-Ching Sang, Isaac D. Hoffman, Gyorgy P. Snell, Keiko Uga, Akira Shibata, Keiko Igaki, Yoshiki Nakamura, Hideyuki Nakagawa, Noboru Tsuchimori, Masashi Yamasaki, Junya Shirai, Satoshi Yamamoto
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.

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