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6-Substituted quinolines as RORγt inverse agonists

DOI: 10.1016/j.bmcl.2017.10.027 DOI Help

Authors: J. Kent Barbay (Janssen Research and Development, LLC) , Maxwell D. Cummings (Janssen Research and Development, LLC) , Marta Abad (Janssen Research and Development, LLC) , Glenda Castro (Janssen Research and Development, LLC) , Kevin D. Kreutter (Janssen Research and Development, LLC) , David A. Kummer (Janssen Research and Development, LLC) , Umar Maharoof (Janssen Research and Development, LLC) , Cynthia Milligan (Janssen Research and Development, LLC) , Rachel Nishimura (Janssen Research and Development, LLC) , Joan Pierce (Janssen Research and Development, LLC) , Celine Schalk-Hihi (Janssen Research and Development, LLC) , John Spurlino (Janssen Research and Development, LLC) , Virginia M. Tanis (Janssen Research and Development, LLC) , Maud Urbanski (Janssen Research and Development, LLC) , Hariharan Venkatesan (Janssen Research and Development, LLC) , Aihua Wang (Janssen Research and Development, LLC) , Craig Woods (Janssen Research and Development, LLC) , Ronald Wolin (Janssen Research and Development, LLC) , Xiaohua Xue (Janssen Research and Development, LLC) , James P. Edwards (Janssen Research and Development, LLC) , Anne M. Fourie (Janssen Research and Development, LLC) , Kristi Leonard (Janssen Research and Development, LLC)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters , VOL 27 , PAGES 5277 - 5283

State: Published (Approved)
Published: December 2017

Abstract: We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). The synthesis of this class of RORγt modulators is reported, and optimization of the substituents at the quinoline 6-position that produced compounds with high affinity for the receptor is detailed. This effort identified molecules that act as potent, full inverse agonists in a RORγt-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the RORγt ligand binding domain are disclosed, and we highlight the interaction of a hydrogen-bond acceptor on the 6-position substituent of the inverse agonist with Glu379:NH as a conserved binding contact.

Journal Keywords: RORγt; Retinoic acid-related orphan nuclear receptor gamma t; Th17; IL-17

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 09/01/2018 08:45

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)