Discovery of 3-Cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yObenzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor Related Orphan Receptor C2 Inverse Agonist

被引：25

作者：

Schnute, Mark E. ^{[1
]}

Wennerstal, Mattias ^{[6
]}

Alley, Jennifer ^{[2
]}

Bengtsson, Martin ^{[6
]}

Blinn, James R. ^{[4
]}

Bolten, Charles W. ^{[5
]}

Braden, Timothy ^{[5
]}

Bonn, Tomas ^{[6
]}

Carlsson, Bo ^{[6
]}

Caspers, Nicole ^{[3
]}

Chen, Ming ^{[3
]}

Choi, Chulho ^{[3
]}

Collis, Leon P. ^{[2
]}

Crouse, Kimberly ^{[2
]}

Farnegardh, Mathias ^{[6
]}

Fennell, Kimberly F. ^{[3
]}

Fish, Susan ^{[2
]}

Flick, Andrew C. ^{[3
]}

Goos-Nilsson, Annika ^{[6
]}

Gullberg, Hjalmar ^{[6
]}

Harris, Peter K. ^{[5
]}

Heasley, Steven E. ^{[3
]}

Hegen, Martin ^{[2
]}

Hromockyj, Alexander E. ^{[5
]}

Hu, Xiao ^{[5
]}

Husman, Bolette ^{[6
]}

Janosik, Tomasz ^{[6
]}

Jones, Peter ^{[1
]}

Kaila, Neelu ^{[1
]}

Kallin, Elisabet ^{[6
]}

Kauppi, Bjorn ^{[6
]}

Kiefer, James R. ^{[4
]}

Knafels, John ^{[3
]}

Koehler, Konrad ^{[6
]}

Kruger, Lars ^{[6
]}

Kurumbail, Ravi G. ^{[3
]}

Kyne, Robert E., Jr. ^{[3
]}

Li, Wei ^{[2
]}

Lofstedt, Joakim ^{[6
]}

Long, Scott A. ^{[4
]}

Menard, Carol A. ^{[3
]}

Mente, Scot

Messing, Dean

Meyers, Marvin J. ^{[4
]}

Napierata, Lee ^{[2
]}

Noteberg, Daniel ^{[6
]}

Nuhant, Philippe ^{[3
]}

Pelc, Matthew J. ^{[4
]}

Prinsen, Michael J. ^{[5
]}

Rhonnstad, Patrik ^{[6
]}

机构：

[1] Pfizer Inc, Med Design, Cambridge, MA 02139 USA

[2] Pfizer Inc, Inflammat & Immunol Res, Cambridge, MA 02139 USA

[3] Pfizer Inc, Med Design, Groton, CT 06340 USA

[4] Pfizer Inc, Worldwide Med Chem, St Louis, MO 63017 USA

[5] Pfizer Inc, Inflammat & Immunol Res, St Louis, MO 63017 USA

[6] Karo Pharma AB, S-11148 Stockholm, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 23期

关键词：

ROR-GAMMA-T; NUCLEAR RECEPTOR; MONOCLONAL-ANTIBODY; DOUBLE-BLIND; SECUKINUMAB; PSORIASIS; IDENTIFICATION; LIGANDS; DIFFERENTIATION; INFLAMMATION;

D O I：

10.1021/acs.jmedchem.8b00392

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as ROR gamma t) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.

引用

页码：10415 / 10439

页数：25

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