Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

  • J Med Chem. 2018 Apr 12;61(7):2973-2988. doi: 10.1021/acs.jmedchem.8b00061.
Mitsunori Kono  1 ,  Atsuko Ochida  1 ,  Tsuneo Oda  1 ,  Takashi Imada  1 ,  Yoshihiro Banno  1 ,  Naohiro Taya  1 ,  Shinichi Masada  1 ,  Tetsuji Kawamoto  1 ,  Kazuko Yonemori  1 ,  Yoshi Nara  1 ,  Yoshiyuki Fukase  1 ,  Tomoya Yukawa  1 ,  Hidekazu Tokuhara  1 ,  Robert Skene  2 ,  Bi-Ching Sang  2 ,  Isaac D Hoffman  2 ,  Gyorgy P Snell  2 ,  Keiko Uga  1 ,  Akira Shibata  1 ,  Keiko Igaki  1 ,  Yoshiki Nakamura  1 ,  Hideyuki Nakagawa  1 ,  Noboru Tsuchimori  1 ,  Masashi Yamasaki  1 ,  Junya Shirai  1 ,  Satoshi Yamamoto  1
Affiliations
  • 1. Pharmaceutical Research Division , Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome , Fujisawa , Kanagawa 251-8555 , Japan.
  • 2. Takeda California , 10410 Science Center Drive , San Diego , California 92121 , United States.
PMID: 29510038 DOI: 10.1021/acs.jmedchem.8b00061
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-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-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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