Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORγt Inverse Agonists

  • ACS Med Chem Lett. 2019 Feb 26;10(3):367-373. doi: 10.1021/acsmedchemlett.9b00010.
James J-W Duan  1 ,  Zhonghui Lu  1 ,  Bin Jiang  1 ,  Sylwia Stachura  1 ,  Carolyn A Weigelt  1 ,  John S Sack  1 ,  Javed Khan  1 ,  Max Ruzanov  1 ,  Michael A Galella  1 ,  Dauh-Rurng Wu  1 ,  Melissa Yarde  1 ,  Ding-Ren Shen  1 ,  David J Shuster  1 ,  Virna Borowski  1 ,  Jenny H Xie  1 ,  Lisa Zhang  1 ,  Sridhar Vanteru  2 ,  Arun Kumar Gupta  2 ,  Arvind Mathur  1 ,  Qihong Zhao  1 ,  William Foster  1 ,  Luisa M Salter-Cid  1 ,  Percy H Carter  1 ,  T G Murali Dhar  1
Affiliations
  • 1. Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
  • 2. Bristol-Myers Squibb-Biocon Research Center, Bangalore 560099, India.
PMID: 30891142 DOI: 10.1021/acsmedchemlett.9b00010
Abstract

A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRβ. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.

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