Open AccessAzatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis
Author(s) -
Qingjie Liu,
Hai-Yun Xiao,
Douglas G. Batt,
Zili Xiao,
Yeheng Zhu,
Michael G. Yang,
Ning Li,
Shiuhang Yip,
Peng Li,
Dawn Sun,
DauhRurng Wu,
Max Ruzanov,
John S. Sack,
Carolyn A. Weigelt,
Jinhong Wang,
Sha Li,
David J. Shuster,
Jenny Xie,
Yunling Song,
Tara Sherry,
Mary Obermeier,
Aberra Fura,
Kevin Stefanski,
Georgia Cornelius,
Silvi A. Chacko,
Purnima Khandelwal,
Shailesh Dudhgaonkar,
Anjuman Rudra,
Jignesh Nagar,
Venkata Murali,
Arun Govindarajan,
Rex Denton,
Qihong Zhao,
Nicholas A. Meanwell,
R. M. Borzilleri,
T. G. Murali Dhar
Publication year - 2021
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.1c00112
Subject(s) - psoriasis , rheumatoid arthritis , potency , inverse agonist , pharmacology , in vivo , quinoline , metabolic stability , agonist , in vitro , medicine , partial agonist , chemistry , pharmacokinetics , stereochemistry , computational biology , combinatorial chemistry , biochemistry , immunology , receptor , biology , organic chemistry , microbiology and biotechnology
Structure-activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by 1 with heterocyclic moieties led to the identification of three novel aza analogs 5 - 7 . The hexahydropyrrolo[3,2- f ]quinoline series 5 (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series 1 but with improved in vitro membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series 3 , culminating in the discovery of 8e as a potent and selective RORγt inverse agonist with an excellent in vitro profile, good pharmacokinetic properties, and biologic-like in vivo efficacy in preclinical models of rheumatoid arthritis and psoriasis.