Open AccessNovel Tricyclic Pyroglutamide Derivatives as Potent RORγt Inverse Agonists Identified using a Virtual Screening Approach
Author(s) -
Qingjie Liu,
Douglas G. Batt,
Carolyn A. Weigelt,
Shiuhang Yip,
DauhRurng Wu,
Max Ruzanov,
John S. Sack,
Jinhong Wang,
Melissa Yarde,
Sha Li,
David J. Shuster,
Jenny Xie,
Tara Sherry,
Mary Obermeier,
Aberra Fura,
Kevin Stefanski,
Georgia Cornelius,
Purnima Khandelwal,
Joseph A. Tino,
John E. Macor,
Luisa Salter–Cid,
Rex Denton,
Qihong Zhao,
T. G. Murali Dhar
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00496
Subject(s) - moiety , prodrug , inverse agonist , tricyclic , virtual screening , chemistry , solubility , stereochemistry , agonist , combinatorial chemistry , rar related orphan receptor gamma , pharmacology , medicine , biochemistry , receptor , organic chemistry , pharmacophore , transcription factor , gene
Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.