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Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-28 , DOI: 10.1021/acs.jmedchem.0c01698 Chunjian Liu 1 , James Lin 1 , Charles Langevine 1 , Daniel Smith 2 , Jianqing Li 2 , John S. Tokarski 3 , Javed Khan 3 , Max Ruzanov 3 , Joann Strnad 4 , Adriana Zupa-Fernandez 4 , Lihong Cheng 4 , Kathleen M. Gillooly 4 , David Shuster 4 , Yifan Zhang 4 , Anil Thankappan 4 , Kim W. McIntyre 4 , Charu Chaudhry 5 , Paul A. Elzinga 6 , Manoj Chiney 6 , Anjaneya Chimalakonda 6 , Louis J. Lombardo 1 , John E. Macor 1 , Percy H. Carter 1 , James R. Burke 4 , David S. Weinstein 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-28 , DOI: 10.1021/acs.jmedchem.0c01698 Chunjian Liu 1 , James Lin 1 , Charles Langevine 1 , Daniel Smith 2 , Jianqing Li 2 , John S. Tokarski 3 , Javed Khan 3 , Max Ruzanov 3 , Joann Strnad 4 , Adriana Zupa-Fernandez 4 , Lihong Cheng 4 , Kathleen M. Gillooly 4 , David Shuster 4 , Yifan Zhang 4 , Anil Thankappan 4 , Kim W. McIntyre 4 , Charu Chaudhry 5 , Paul A. Elzinga 6 , Manoj Chiney 6 , Anjaneya Chimalakonda 6 , Louis J. Lombardo 1 , John E. Macor 1 , Percy H. Carter 1 , James R. Burke 4 , David S. Weinstein 1
Affiliation
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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.
中文翻译：
BMS-986202的发现：与Tyk2 JH2结合的临床Tyk2抑制剂
从6（BMS-986165）（一种哒嗪羧酰胺衍生的Tyk2 JH2配体，目前正在开发用于治疗牛皮癣的临床Tyk2抑制剂）中寻找结构上多样化的Tyk2 JH2配体，是从对6个成员的六元杂芳基进行的调查开始的代替的ñ在甲基三唑基部分6。早期铅（12）的X射线共晶体结构揭示了潜在的新结合口袋。对新口袋的探索导致两名临床候选人获得领先。通过叔酰胺部分实现了与囊中Thr599的潜在氢键相互作用，这一点由29的X射线共晶体结构证实。当多样性搜索扩展到烟酰胺时，发现单个氟原子添加可显着增强通透性，这直接导致发现7（BMS-986202）作为与Tyk2 JH2结合的临床Tyk2抑制剂。也将介绍7的临床前研究，包括在IL-23驱动的棘皮症，抗CD40诱导的结肠炎和自发性狼疮的小鼠模型中的功效研究。
更新日期：2021-01-14
中文翻译：
BMS-986202的发现：与Tyk2 JH2结合的临床Tyk2抑制剂
从6（BMS-986165）（一种哒嗪羧酰胺衍生的Tyk2 JH2配体，目前正在开发用于治疗牛皮癣的临床Tyk2抑制剂）中寻找结构上多样化的Tyk2 JH2配体，是从对6个成员的六元杂芳基进行的调查开始的代替的ñ在甲基三唑基部分6。早期铅（12）的X射线共晶体结构揭示了潜在的新结合口袋。对新口袋的探索导致两名临床候选人获得领先。通过叔酰胺部分实现了与囊中Thr599的潜在氢键相互作用，这一点由29的X射线共晶体结构证实。当多样性搜索扩展到烟酰胺时，发现单个氟原子添加可显着增强通透性，这直接导致发现7（BMS-986202）作为与Tyk2 JH2结合的临床Tyk2抑制剂。也将介绍7的临床前研究，包括在IL-23驱动的棘皮症，抗CD40诱导的结肠炎和自发性狼疮的小鼠模型中的功效研究。
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