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    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.

    Citation

    Chunjian Liu, James Lin, Charles Langevine, Daniel Smith, Jianqing Li, John S Tokarski, Javed Khan, Max Ruzanov, Joann Strnad, Adriana Zupa-Fernandez, Lihong Cheng, Kathleen M Gillooly, David 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. Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2. Journal of medicinal chemistry. 2021 Jan 14;64(1):677-694

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    PMID: 33370104

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