Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-γt (RORγt) agonists

被引：5

作者：

Ruan, Zheming ^{[1
]}

Park, Peter K. ^{[1
]}

Wei, Donna ^{[1
]}

Purandare, Ashok ^{[1
]}

Wan, Honghe ^{[1
]}

O'Malley, Daniel ^{[1
]}

Stachura, Sylwia ^{[1
]}

Perez, Heidi ^{[1
]}

Cavallaro, Cullen L. ^{[1
]}

Weigelt, Carolyn A. ^{[2
]}

Sack, John S. ^{[2
]}

Ruzanov, Max ^{[2
]}

Khan, Javed ^{[2
]}

Gururajan, Murali ^{[3
]}

Wong, Jessica J. ^{[3
]}

Huang, Yanling ^{[3
]}

Yarde, Melissa ^{[4
]}

Li, Zhuyin ^{[4
]}

Chen, Cliff ^{[5
]}

Sun, Huadong ^{[5
]}

Borowski, Virna ^{[6
]}

Xie, Jenny H. ^{[6
]}

Anthony, Monique ^{[4
]}

Agler, Michele ^{[4
]}

Fink, Brian E. ^{[1
]}

Harikrishnan, Lalgudi S. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Dept Chem, POB 4000, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Co, Mol Struct & Design, POB 4000, Princeton, NJ USA

[3] Bristol Myers Squibb Co, Immunooncol Small Mol Biol, POB 4000, Princeton, NJ USA

[4] Bristol Myers Squibb Co, Lead Discovery & Optimizat, POB 4000, Princeton, NJ USA

[5] Bristol Myers Squibb Co, Preclin Candidate Optimizat, POB 4000, Princeton, NJ USA

[6] Bristol Myers Squibb Co, Vivo Pharmacol, POB 4000, Princeton, NJ USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2021年 / 35卷

关键词：

ROR gamma t; RORgt; ROR gamma; Retinoic acid related-orphan receptor; Th 17 cells and IL-17;

D O I：

10.1016/j.bmcl.2021.127778

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor gamma t (ROR gamma t) agonists is described. Compound 1 was identified from deck mining as a ROR gamma t agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. (C) 2020 Elsevier Science Ltd. All rights reserved.

引用

页数：6

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