Tricyclic-Carbocyclic RORγt Inverse AgonistsDiscovery of BMS-986313
datasetposted on 16.02.2021, 19:05 by Michael G. Yang, Myra Beaudoin-Bertrand, Zili Xiao, David Marcoux, Carolyn A. Weigelt, Shiuhang Yip, Dauh-Rurng Wu, Max Ruzanov, John S. Sack, Jinhong Wang, Melissa Yarde, Sha Li, David J. Shuster, Jenny H. Xie, Tara Sherry, Mary T. Obermeier, Aberra Fura, Kevin Stefanski, Georgia Cornelius, Purnima Khandelwal, Ananta Karmakar, Mushkin Basha, Venkatesh Babu, Arun Kumar Gupta, Arvind Mathur, Luisa Salter-Cid, Rex Denton, Qihong Zhao, T. G. Murali Dhar
SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3–7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasisthe IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.