Identification and structure activity relationships of quinoline tertiary alcohol modulators of RORγt

David A Kummer; Maxwell D Cummings; Marta Abad; Joseph Barbay; Glenda Castro; Ronald Wolin; Kevin D Kreutter; Umar Maharoof; Cynthia Milligan; Rachel Nishimura; Joan Pierce; Celine Schalk-Hihi; John Spurlino; Maud Urbanski; Hariharan Venkatesan; Aihua Wang; Craig Woods; Xiaohua Xue; James P Edwards; Anne M Fourie; Kristi Leonard

doi:10.1016/j.bmcl.2017.02.044

Identification and structure activity relationships of quinoline tertiary alcohol modulators of RORγt

Bioorg Med Chem Lett. 2017 May 1;27(9):2047-2057. doi: 10.1016/j.bmcl.2017.02.044. Epub 2017 Feb 21.

Authors

David A Kummer¹, Maxwell D Cummings², Marta Abad³, Joseph Barbay⁴, Glenda Castro⁵, Ronald Wolin⁵, Kevin D Kreutter⁴, Umar Maharoof⁴, Cynthia Milligan³, Rachel Nishimura⁵, Joan Pierce⁵, Celine Schalk-Hihi³, John Spurlino³, Maud Urbanski⁴, Hariharan Venkatesan⁵, Aihua Wang⁴, Craig Woods⁵, Xiaohua Xue⁵, James P Edwards⁵, Anne M Fourie⁵, Kristi Leonard⁶

Affiliations

¹ Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address: [email protected].
² Discovery Sciences, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States. Electronic address: [email protected].
³ Discovery Sciences, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
⁴ Discovery Immunology, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
⁵ Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
⁶ Discovery Immunology, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States. Electronic address: [email protected].

PMID: 28318945
DOI: 10.1016/j.bmcl.2017.02.044

Abstract

A high-throughput screen of the ligand binding domain of the nuclear receptor retinoic acid-related orphan receptor gamma t (RORγt) employing a thermal shift assay yielded a quinoline tertiary alcohol hit. Optimization of the 2-, 3- and 4-positions of the quinoline core using structure-activity relationships and structure-based drug design methods led to the discovery of a series of modulators with improved RORγt inhibitory potency and inverse agonism properties.

Keywords: Agonist; IL-17; Inverse agonist; Neutral antagonist; RORγt; Retinoic acid-related orphan nuclear receptor gamma t; Th17.

MeSH terms

Drug Design*
Drug Inverse Agonism*
Humans
Molecular Docking Simulation
Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors*
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
Quinolines / chemistry*
Quinolines / pharmacology*
Structure-Activity Relationship
Th17 Cells / drug effects

Substances

Nuclear Receptor Subfamily 1, Group F, Member 3
Quinolines