Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis

  • ACS Med Chem Lett. 2021 Apr 30;12(5):827-835. doi: 10.1021/acsmedchemlett.1c00112.
Qingjie Liu  1 ,  Hai-Yun Xiao  1 ,  Douglas G Batt  1 ,  Zili Xiao  1 ,  Yeheng Zhu  1 ,  Michael G Yang  1 ,  Ning Li  1 ,  Shiuhang Yip  1 ,  Peng Li  1 ,  Dawn Sun  1 ,  Dauh-Rurng Wu  1 ,  Max Ruzanov  1 ,  John S Sack  1 ,  Carolyn A Weigelt  1 ,  Jinhong Wang  1 ,  Sha Li  1 ,  David J Shuster  1 ,  Jenny H Xie  1 ,  Yunling Song  1 ,  Tara Sherry  1 ,  Mary T Obermeier  1 ,  Aberra Fura  1 ,  Kevin Stefanski  1 ,  Georgia Cornelius  1 ,  Silvi Chacko  1 ,  Purnima Khandelwal  1 ,  Shailesh Dudhgaonkar  2 ,  Anjuman Rudra  2 ,  Jignesh Nagar  2 ,  Venkata Murali  2 ,  Arun Govindarajan  2 ,  Rex Denton  1 ,  Qihong Zhao  1 ,  Nicholas A Meanwell  1 ,  Robert Borzilleri  1 ,  T G Murali Dhar  1
Affiliations
  • 1. Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
  • 2. Biocon Bristol Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
PMID: 34055233 DOI: 10.1021/acsmedchemlett.1c00112
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.

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