Rationally Designed, Conformationally Constrained Inverse Agonists of RORγt-Identification of a Potent, Selective Series with Biologic-Like in Vivo Efficacy.
David MarcouxJames J-W DuanQing ShiRobert J CherneyAnurag S SrivastavaLyndon CorneliusDouglas G BattQingjie LiuMyra Beaudoin-BertrandCarolyn A WeigeltPurnima KhandelwalSureshbabu VishwakrishnanKumaravel SelvakumarAnanta KarmakarArun Kumar GuptaMushkin BashaSridharan RamlingamNaveen ManjunathSridhar VanteruSukhen KarmakarNageswara MaddalaVetrichelvan MuthalaguAnuradha GuptaRichard A RampullaArvind MathurShiuhang YipPeng LiDauh-Rurng WuJaved KhanMax RuzanovJohn S SackJinhong WangMelissa YardeMary Ellen CvijicSha LiDavid J ShusterVirna BorowskiJenny H XieKim W McIntyreMary T ObermeierAberra FuraKevin StefanskiGeorgia CorneliusJohn HynesJoseph A TinoJohn E MacorLuisa Salter-CidRex DentonQihong ZhaoPercy H CarterT G Murali DharPublished in: Journal of medicinal chemistry (2019)
RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.