1. Academic Validation
  2. Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis

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

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.
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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