Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis.
Qingjie LiuHai-Yun XiaoDouglas G BattZili XiaoYeheng ZhuMichael G YangNing LiShiuhang YipPeng LiDawn SunDauh-Rurng WuMax RuzanovJohn S SackCarolyn A WeigeltJinhong WangSha LiDavid J ShusterJenny H XieYunling SongTara SherryMary T ObermeierAberra FuraKevin StefanskiGeorgia CorneliusSilvi ChackoPurnima KhandelwalShailesh DudhgaonkarAnjuman RudraJignesh NagarVenkata MuraliArun GovindarajanRex DentonQihong ZhaoNicholas A MeanwellRobert BorzilleriT G Murali DharPublished in: ACS medicinal chemistry letters (2021)
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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