2. Academic Validation
  3. 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

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

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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