Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists

被引：64

作者：

Fauber, Benjamin P. ^{[1
]}

Gobbi, Alberto ^{[1
]}

Robarge, Kirk ^{[1
]}

Zhou, Aihe ^{[1
]}

Barnard, Adrian ^{[2
]}

Cao, Jianhua ^{[3
]}

Deng, Yuzhong ^{[1
]}

Eidenschenk, Celine ^{[1
]}

Everett, Christine ^{[1
]}

Ganguli, Arunima ^{[2
]}

Hawkins, Julie ^{[2
]}

Johnson, Adam R. ^{[1
]}

La, Hank ^{[1
]}

Norman, Maxine ^{[2
]}

Salmon, Gary ^{[2
]}

Summerhill, Susan ^{[2
]}

Ouyang, Wenjun ^{[1
]}

Tang, Wei ^{[3
]}

Wong, Harvey ^{[1
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

[2] Argenta, Harlow CM19 5TR, Essex, England

[3] ChemPartner, Shanghai 201203, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 15期

关键词：

RORc; ROR gamma; IL-17; PPAR gamma; GNE-0946; GNE-6468; ORPHAN NUCLEAR RECEPTORS; GAMMA-T; MODULATORS; DIFFERENTIATION; AUTOIMMUNE; ANTIBODY; CELLS; PERMEABILITY; SECUKINUMAB; METABOLISM;

D O I：

10.1016/j.bmcl.2015.05.055

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The nuclear receptor (NR) retinoic acid receptor-related orphan receptor gamma (ROR gamma, RORc, or NR1F3) is a promising target for the treatment of autoimmune diseases. RORc is a critical regulator in the production of the pro-inflammatory cytokine interleukin-17. We discovered a series of potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists. The most potent compounds displayed >300-fold selectivity for RORc over the other ROR family members, PPAR gamma, and NRs in our cellular selectivity panel. The favorable potency, selectivity, and physiochemical properties of GNE-0946 (9) and GNE-6468 (28), in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：2907 / 2912

页数：6

共 46 条

[1] Benzoyl 2-methyl indoles as selective PPARγ modulators [J].

Acton, JJ ;

Black, RM ;

Jones, AB ;

Moller, DE ;

Colwell, L ;

Doebber, TW ;

MacNaul, KL ;

Berger, J ;

Wood, HB .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (02) :357-362

[2] Discovery of (2R)-2-(3-{3-[(4-Methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic Acid (MK-0533): A Novel Selective Peroxisome Proliferator-Activated Receptor γ Modulator for the Treatment of Type 2 Diabetes Mellitus with a Reduced Potential to Increase Plasma and Extracellular Fluid Volume [J].

Acton, John J., III ;

Akiyama, Taro E. ;

Chang, Ching H. ;

Colwell, Lawrence ;

Debenham, Sheryl ;

Doebber, Thomas ;

Einstein, Monica ;

Liu, Kun ;

McCann, Margaret E. ;

Moller, David E. ;

Muise, Eric S. ;

Tan, Yugen ;

Thompson, John R. ;

Wong, Kenny K. ;

Wu, Margaret ;

Xu, Libo ;

Meinke, Peter T. ;

Berger, Joel P. ;

Wood, Harold B. .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (13) :3846-3854

[3] Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial [J].

Baeten, Dominique ;

Baraliakos, Xenofon ;

Braun, Juergen ;

Sieper, Joachim ;

Emery, Paul ;

van der Heijde, Desiree ;

McInnes, Iain ;

van Laar, Jacob M. ;

Landewe, Robert ;

Wordsworth, Paul ;

Wollenhaupt, Juergen ;

Kellner, Herbert ;

Paramarta, Jacqueline ;

Wei, Jiawei ;

Brachat, Arndt ;

Bek, Stephan ;

Laurent, Didier ;

Li, Yali ;

Wang, Ying A. ;

Bertolino, Arthur P. ;

Gsteiger, Sandro ;

Wright, Andrew M. ;

Hueber, Wolfgang .

LANCET, 2013, 382 (9906) :1705-1713

[4]

Barr K. J., 2014, W.O. Patent, Patent No. [2014/028600, 2014028600]

[5] Targeting the IL-17-TH17 pathway [J].

Bartlett, Hilary S. ;

Million, Ryan P. .

NATURE REVIEWS DRUG DISCOVERY, 2015, 14 (01) :11-12

[6]

Chaudhari S.S., 2015, PCT Int. Appl, Patent No. [2015/008234, 2015008234]

[7] Development and regulation of RORγt+ innate lymphoid cells [J].

Cording, Sascha ;

Medvedovic, Jasna ;

Cherrier, Marie ;

Eberl, Gerard .

FEBS LETTERS, 2014, 588 (22) :4176-4181

[8] Molecular fields in quantitative structure-permeation relationships: the VolSurf approach [J].

Cruciani, C ;

Crivori, P ;

Carrupt, PA ;

Testa, B .

JOURNAL OF MOLECULAR STRUCTURE-THEOCHEM, 2000, 503 (1-2) :17-30

[9]

Das S., 2015, PCT Int. Appl, Patent No. [2015/052675, 2015052675]

[10] Targeting the Nuclear Hormone Receptor RORγt for the Treatment of Autoimmune and Inflammatory Disorders [J].

Dhar, T. G. Murali ;

Zhao, Qihong ;

Markby, David W. .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 48, 2013, 48 :169-182

← 1 2 3 4 5 →