Defining Target Engagement Required for Efficacy In Vivo at the Retinoic Acid Receptor-Related Orphan Receptor C2 (RORγt)

被引：4

作者：

Lugar, Charles W. ^{[1
]}

Clarke, Christian A. ^{[1
]}

Morphy, Richard ^{[1
]}

Rudyk, Helene ^{[1
]}

Sapmaz, Selma ^{[1
]}

Stites, Ryan E. ^{[1
]}

Vaught, Grant M. ^{[1
]}

Furness, Kelly ^{[1
]}

Broughton, Howard B. ^{[1
]}

Durst, Greg L. ^{[1
]}

Clawson, David K. ^{[1
]}

Stout, Stephanie L. ^{[1
]}

Guo, Sherry Y. ^{[1
]}

Durbin, Jim D. ^{[1
]}

Stayrook, Keith R. ^{[1
]}

Edmondson, Denise D. ^{[1
]}

Kikly, Kristy ^{[1
]}

New, Nicole E. ^{[1
]}

Bina, Holly A. ^{[1
]}

Chambers, Mark G. ^{[1
]}

Shetler, Pamela ^{[1
]}

Chang, William Y. ^{[2
]}

Chang, Veavi Ching-Yun ^{[1
]}

Barr, Rob ^{[1
]}

Gough, Wendy H. ^{[1
]}

Steele, Jimmy P. ^{[1
]}

Getman, Brian ^{[1
]}

Patel, Nita ^{[1
]}

Mathes, Brian M. ^{[1
]}

Richardson, Timothy, I ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

[2] Eli Lilly & Co, Lilly Biotechnol Ctr, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 09期

关键词：

NUCLEAR RECEPTOR; INTRINSIC CLEARANCE; METABOLIC-CLEARANCE; PLASMA-PROTEIN; BINDING; LIGANDS; MODULATORS; INDUCTION; ARTHRITIS; INSIGHTS;

D O I：

10.1021/acs.jmedchem.0c01918

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (ROR gamma t) is a master regulator of Th17 cells and controls the expression of IL-17A. ROR gamma t is expressed primarily in IL-17A-producing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-2'-carboxamide scaffold as a starting point for optimization of binding affinity and functional activity guided by structure-based design. Compound 12 demonstrated activity in a mouse PK/PD model and efficacy in an inflammatory arthritis mouse model that were used to define the level and duration of target engagement required for efficacy in vivo. Further optimization to improve ADME and physicochemical properties with guidance from simulations and modeling provided compound 22, which is projected to achieve the level and duration of target engagement required for efficacy in the clinic.

引用

页码：5470 / 5484

页数：15

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