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

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

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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