6-Substituted quinolines as RORγt inverse agonists

被引：20

作者：

Barbay, J. Kent ^{[3
]}

Cummings, Maxwell D. ^{[2
]}

Abad, Marta ^{[2
]}

Castro, Glenda ^{[1
]}

Kreutter, Kevin D. ^{[3
]}

Kummer, David A. ^{[1
]}

Maharoof, Umar ^{[3
]}

Milligan, Cynthia ^{[2
]}

Nishimura, Rachel ^{[1
]}

Pierce, Joan ^{[1
]}

Schalk-Hihi, Celine ^{[2
]}

Spurlino, John ^{[2
]}

Tanis, Virginia M. ^{[1
]}

Urbanski, Maud ^{[3
]}

Venkatesan, Hariharan ^{[1
]}

Wang, Aihua ^{[3
]}

Woods, Craig ^{[1
]}

Wolin, Ronald ^{[1
]}

Xue, Xiaohua ^{[1
]}

Edwards, James P. ^{[1
]}

Fourie, Anne M. ^{[1
]}

Leonard, Kristi ^{[3
]}

机构：

[1] Janssen Res & Dev LLC, Discovery Immunol, 3210 Merryfield Row, San Diego, CA 92121 USA

[2] Janssen Res & Dev LLC, Discovery Sci, Welsh & McKean Rd, Spring House, PA 19477 USA

[3] Janssen Res & Dev LLC, Discovery Immunol, Welsh & McKean Rd, Spring House, PA 19477 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 23期

关键词：

ROR gamma t; Retinoic acid-related orphan nuclear; receptor gamma t; Th17; IL-17; ORPHAN RECEPTORS; STRUCTURAL BASIS; MODULATORS; DIFFERENTIATION; PSORIASIS; LIGANDS; IL-17; CELLS;

D O I：

10.1016/j.bmcl.2017.10.027

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (ROR gamma t). The synthesis of this class of ROR gamma t 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 ROR gamma t-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the ROR gamma t 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. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：5277 / 5283

页数：7

共 20 条

[1]

Barbay JK, PCT Int. Appl., Patent No. [WO 2015057203, 2015057203]

[2]

A Review of Biologic Therapies Targeting IL-23 and IL-17 for Use in Moderate-to-Severe Plaque Psoriasis [J].

Campa, Molly ;

Mansouri, Bobbak ;

Warren, Richard ;

Menter, Alan .

DERMATOLOGY AND THERAPY, 2016, 6 (01) :1-12

[3]

Modulators of the Nuclear Receptor Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc) [J].

Fauber, Benjamin P. ;

Magnuson, Steven .

JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (14) :5871-5892

[4]

Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases [J].

Fragoulis, George E. ;

Siebert, Stefan ;

McInnes, Iain B. .

ANNUAL REVIEW OF MEDICINE, VOL 67, 2016, 67 :337-353

[5]

Structural Basis of Digoxin That Antagonizes RORγt Receptor Activity and Suppresses Th17 Cell Differentiation and Interleukin (IL)-17 Production [J].

Fujita-Sato, Saori ;

Ito, Shuichiro ;

Isobe, Takashi ;

Ohyama, Takao ;

Wakabayashi, Kenji ;

Morishita, Kaoru ;

Ando, Osamu ;

Isono, Fujio .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (36) :31409-31417

[6]

TANDEM ORGANOMETALLIC ADDITION-REACTIONS TO N-METHOXY-UREAS AND URETHANES IN THE PREPARATION OF UNSYMMETRICAL AND SYMMETRICAL KETONES [J].

HLASTA, DJ ;

COURT, JJ .

TETRAHEDRON LETTERS, 1989, 30 (14) :1773-1776

[7]

The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells [J].

Ivanov, Ivaylo I. ;

McKenzie, Brent S. ;

Zhou, Liang ;

Tadokoro, Carlos E. ;

Lepelley, Alice ;

Lafaille, Juan J. ;

Cua, Daniel J. ;

Littman, Dan R. .

CELL, 2006, 126 (06) :1121-1133

[8]

Jetten Anton M, 2009, Nucl Recept Signal, V7, pe003, DOI 10.1621/nrs.07003

[9]

Structural Basis for Hydroxycholesterols as Natural Ligands of Orphan Nuclear Receptor RORγ [J].

Jin, Lihua ;

Martynowski, Dariusz ;

Zheng, Songyang ;

Wada, Taira ;

Xie, Wen ;

Li, Yong .

MOLECULAR ENDOCRINOLOGY, 2010, 24 (05) :923-929

[10]

Synthetic modulators of the retinoic acid receptor-related orphan receptors [J].

Kamenecka, Theodore M. ;

Lyda, Brent ;

Chang, Mi Ra ;

Griffin, Patrick R. .

MEDCHEMCOMM, 2013, 4 (05) :764-776

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