Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists. Issue 16 (15th August 2019)

• Record Type: Journal Article
• Authors: Lu, Zhonghui; Duan, James J.-W.; Xiao, Haiyun; Neels, James; Wu, Dauh-Rurng; Weigelt, Carolyn A.; Sack, John S.; Khan, Javed; Ruzanov, Max; An, Yongmi; Yarde, Melissa; Karmakar, Ananta; Vishwakrishnan, Sureshbabu; Baratam, Venkata; Shankarappa, Harisha; Vanteru, Sridhar; Babu, Venkatesh; Basha, Mushkin; Kumar Gupta, Arun; Kumaravel, Selvakumar; Mathur, Arvind; Zhao, Qihong; Salter-Cid, Luisa M.; Carter, Percy H.; Murali Dhar, T.G.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 16(2019)
• Page Start: 2265
• Page End: 2269
• Publication Date: 2019-08-15
• Subjects: RORγt -- Retinoic acid-related orphan receptor gamma t -- Inverse agonist -- Th17 -- IL-17; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.06.036
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37 . Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2 .