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Publication Abstract from PubMed

We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORgammat). The synthesis of this class of RORgammat 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 RORgammat-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the RORgammat 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.

6-Substituted quinolines as RORgammat inverse agonists.,Barbay JK, Cummings MD, Abad M, Castro G, Kreutter KD, Kummer DA, Maharoof U, Milligan C, Nishimura R, Pierce J, Schalk-Hihi C, Spurlino J, Tanis VM, Urbanski M, Venkatesan H, Wang A, Woods C, Wolin R, Xue X, Edwards JP, Fourie AM, Leonard K Bioorg Med Chem Lett. 2017 Dec 1;27(23):5277-5283. doi:, 10.1016/j.bmcl.2017.10.027. Epub 2017 Oct 16. PMID:29079472^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.