| Literature DB >> 34055233 |
Qingjie Liu1, Hai-Yun Xiao1, Douglas G Batt1, Zili Xiao1, Yeheng Zhu1, Michael G Yang1, Ning Li1, Shiuhang Yip1, Peng Li1, Dawn Sun1, Dauh-Rurng Wu1, Max Ruzanov1, John S Sack1, Carolyn A Weigelt1, Jinhong Wang1, Sha Li1, David J Shuster1, Jenny H Xie1, Yunling Song1, Tara Sherry1, Mary T Obermeier1, Aberra Fura1, Kevin Stefanski1, Georgia Cornelius1, Silvi Chacko1, Purnima Khandelwal1, Shailesh Dudhgaonkar2, Anjuman Rudra2, Jignesh Nagar2, Venkata Murali2, Arun Govindarajan2, Rex Denton1, Qihong Zhao1, Nicholas A Meanwell1, Robert Borzilleri1, T G Murali Dhar1.
Abstract
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.Entities:
Year: 2021 PMID： 34055233 PMCID： PMC8155243 DOI： 10.1021/acsmedchemlett.1c00112
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345