1区 · 医学
Article
作者: Langevine, Charles ; Lin, James ; Smith, Daniel ; Khan, Javed ; Zupa-Fernandez, Adriana ; Elzinga, Paul A. ; Shuster, David ; Carter, Percy H. ; Chiney, Manoj ; Tokarski, John S. ; Gillooly, Kathleen M. ; Lombardo, Louis J. ; McIntyre, Kim W. ; Liu, Chunjian ; Thankappan, Anil ; Macor, John E. ; Chaudhry, Charu ; Cheng, Lihong ; Weinstein, David S. ; Ruzanov, Max ; Strnad, Joann ; Burke, James R. ; Zhang, Yifan ; Li, Jianqing ; Chimalakonda, Anjaneya
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.