2. Academic Validation
  3. Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists

Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists

  • ChemMedChem. 2019 Nov 20;14(22):1917-1932. doi: 10.1002/cmdc.201900416.
Ayumu Sato 1 2,  Yoshiyuki Fukase 1 3,  Mitsunori Kono 1,  Atsuko Ochida 1,  Tsuneo Oda 1,  Yusuke Sasaki 1,  Naoki Ishii 1,  Yoshihide Tomata 1,  Shoji Fukumoto 1 4,  Yumi N Imai 1 5,  Keiko Uga 1 2,  Akira Shibata 1,  Masashi Yamasaki 1 2,  Hideyuki Nakagawa 1,  Mikio Shirasaki 1 2,  Robert Skene 6,  Isaac Hoffman 6,  Bi-Ching Sang 6,  Gyorgy Snell 6,  Junya Shirai 1 7,  Satoshi Yamamoto 1
Affiliations

Affiliations

  • 1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.
  • 2 Axcelead Drug Discovery Partners, Inc., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-0012, Japan.
  • 3 Tri-Institutional Therapeutics Discovery Institute, Inc., 413 East 69th Street, New York, NY 10021, USA.
  • 4 Japan Tobacco Inc., Central Pharmaceutical Research Institute, 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
  • 5 Chordia Therapeutics Inc., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-0012, Japan.
  • 6 Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
  • 7 Cardurion Pharmaceuticals K.K., 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.
PMID: 31659845 DOI: 10.1002/cmdc.201900416
Abstract

Retinoic-acid-related orphan receptor γt (RORγt) inverse agonists could be used for the treatment of autoimmune diseases. Previously, we reported a novel quinazolinedione 1 a with a flexible linear linker as a novel RORγt inverse agonist. A U-shaped conformation in the complex structure of 1 a with RORγt protein was confirmed. Further improvement of the pharmacokinetic (PK) profiles was required because of the low drug exposure in mice upon oral administration (mouse AUC of 1 a: 27 ng ⋅ h ⋅ mL-1 at 1 mg ⋅ kg-1 , p.o.). To improve the PK profiles, conformationally constrained U-shaped scaffolds were investigated. As a result, morpholine analogues with improved PK profiles and high potency were successfully identified. The substituent at the N1 position of the quinazoline moiety was also modified, leading to an enhancement of reporter activity. Consequently, compound 43 (N2 -(3-chloro-4-cyanophenyl)-N4 -(3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)morpholine-2,4-dicarboxamide) exhibited improved drug exposure (mouse AUC: 1289 ng ⋅ h ⋅ mL-1 at 1 mg ⋅ kg-1 , p.o.). In addition, suppression of IL-17A gene expression by IL-23 stimulation in a mouse pharmacodynamics model was observed for 43. The conformation of 43 with RORγt protein was also confirmed as U-shape by X-ray co-crystal structure analysis. The key interaction that boosts potency is also discussed.

Keywords

RORγ; conformationally constrained scaffolds; interleukin 17; inverse agonists; u-shaped.

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