Identification and structure activity relationships of quinoline tertiary alcohol modulators of RORγt.
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.
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address: dkummer1@its.jnj.com.
David A
DA
Kummer
Discovery Sciences, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States. Electronic address: mcummin1@its.jnj.com.
Maxwell D
MD
Cummings
Discovery Sciences, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
Marta
M
Abad
Discovery Immunology, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
Joseph
J
Barbay
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
Glenda
G
Castro
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
Ronald
R
Wolin
Discovery Immunology, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
Kevin D
KD
Kreutter
Discovery Immunology, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
Umar
U
Maharoof
Discovery Sciences, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
Cynthia
C
Milligan
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
Rachel
R
Nishimura
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
Joan
J
Pierce
Discovery Sciences, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
Celine
C
Schalk-Hihi
Discovery Sciences, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
John
J
Spurlino
Discovery Immunology, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
Maud
M
Urbanski
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
Hariharan
H
Venkatesan
Discovery Immunology, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.
Aihua
A
Wang
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
Craig
C
Woods
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
Xiaohua
X
Xue
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
James P
JP
Edwards
Discovery Immunology, Janssen Research and Development, 3210 Merryfield Row, San Diego, CA 92121, United States.
Anne M
AM
Fourie
Discovery Immunology, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States. Electronic address: kleonar1@its.jnj.com.
Kristi
K
Leonard
D015195:Drug Design; D054314:Drug Inverse Agonism; D006801:Humans; D062105:Molecular Docking Simulation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D058504:Th17 Cells / Q000187:drug effects
D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011804:Quinolines
Agonist; IL-17; Inverse agonist; Neutral antagonist; RORγt; Retinoic acid-related orphan nuclear receptor gamma t; Th17