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6-Substituted quinolines as RORγt inverse agonists. 2017
J Kent Barbay, and
Maxwell D Cummings, and
Marta Abad, and
Glenda Castro, and
Kevin D Kreutter, and
David A Kummer, and
Umar Maharoof, and
Cynthia Milligan, and
Rachel Nishimura, and
Joan Pierce, and
Celine Schalk-Hihi, and
John Spurlino, and
Virginia M Tanis, and
Maud Urbanski, and
Hariharan Venkatesan, and
Aihua Wang, and
Craig Woods, and
Ronald Wolin, and
Xiaohua Xue, and
James P Edwards, and
Anne M Fourie, and
Kristi Leonard
Discovery Immunology, Janssen Research and Development, LLC, Welsh and McKean Roads, Spring House, PA 19477, United States. Electronic address: kbarbay@its.jnj.com.
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.
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