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Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists
Author(s) -
Sato Ayumu,
Fukase Yoshiyuki,
Kono Mitsunori,
Ochida Atsuko,
Oda Tsuneo,
Sasaki Yusuke,
Ishii Naoki,
Tomata Yoshihide,
Fukumoto Shoji,
Imai Yumi N.,
Uga Keiko,
Shibata Akira,
Yamasaki Masashi,
Nakagawa Hideyuki,
Shirasaki Mikio,
Skene Robert,
Hoffman Isaac,
Sang BiChing,
Snell Gyorgy,
Shirai Junya,
Yamamoto Satoshi
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900416
Subject(s) - morpholine , chemistry , inverse agonist , rar related orphan receptor gamma , orphan receptor , stereochemistry , moiety , potency , linker , agonist , pharmacokinetics , retinoic acid , receptor , pharmacology , biochemistry , medicine , gene , medicinal chemistry , in vitro , transcription factor , computer science , operating system
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 ( N 2 ‐(3‐chloro‐4‐cyanophenyl)‐ N 4 ‐(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.