Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2
Chunjian Liu, James C. Lin, Charles M. Langevine, Daniel Smith, Jianqing Li, John S. Tokarski, Javed Khan, Max Ruzanov, Joann Strnad, Adriana Zupa-Fernandez, Lihong Cheng, Kathleen M. Gillooly, David J. Shuster, Yifan Zhang, Anil Thankappan, Kim W. McIntyre, Charu Chaudhry, Paul A. Elzinga, Manoj Chiney, Anjaneya Chimalakonda, Louis J. Lombardo, John E. Macor, Percy H. Carter, James R. Burke, David S. Weinstein
Abstract
A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.