Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Aug 15;29(16):2265-2269.
doi: 10.1016/j.bmcl.2019.06.036. Epub 2019 Jun 20.

Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists

Zhonghui Lu  1 , James J-W Duan  2 , Haiyun Xiao  3 , James Neels  3 , Dauh-Rurng Wu  3 , Carolyn A Weigelt  3 , John S Sack  3 , Javed Khan  3 , Max Ruzanov  3 , Yongmi An  3 , Melissa Yarde  3 , Ananta Karmakar  4 , Sureshbabu Vishwakrishnan  4 , Venkata Baratam  4 , Harisha Shankarappa  4 , Sridhar Vanteru  4 , Venkatesh Babu  4 , Mushkin Basha  4 , Arun Kumar Gupta  4 , Selvakumar Kumaravel  4 , Arvind Mathur  3 , Qihong Zhao  3 , Luisa M Salter-Cid  3 , Percy H Carter  3 , T G Murali Dhar  3
Affiliations

Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists

Zhonghui Lu et al. Bioorg Med Chem Lett. .

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.

Keywords: IL-17; Inverse agonist; RORγt; Retinoic acid-related orphan receptor gamma t; Th17.

PubMed Disclaimer

LinkOut - more resources