Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
Department of Discovery Synthesis, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
J Med Chem. 2021 Jan 14;64(1):677-694. doi: 10.1021/acs.jmedchem.0c01698. Epub 2020 Dec 28.
A search for structurally diversified Tyk2 JH2 ligands from (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 -methyl triazolyl moiety in . The X-ray co-crystal structure of an early lead () 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 . 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 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of , including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.
从吡嗪甲酰胺衍生的 Tyk2 JH2 配体 BMS-986165 中寻找结构多样化的 Tyk2 JH2 配体，该配体目前处于晚期开发阶段，用于治疗银屑病，作为一种临床 Tyk2 抑制剂。我们开始调查了六元杂芳基取代 BMS-986165 中的 -甲基三唑基部分。早期先导化合物（）的 X 射线共晶结构揭示了一个潜在的新结合口袋。对新口袋的探索产生了两个临床候选药物的领跑者。口袋中与 Thr599 的潜在氢键相互作用是通过叔酰胺部分实现的，这通过 X 射线共晶结构得到了证实。当对烟酰胺进行多样性搜索时，发现添加一个氟原子可显著提高通透性，这直接导致了临床 Tyk2 抑制剂 BMS-986202 的发现，该抑制剂与 Tyk2 JH2 结合。还将介绍 BMS-986202 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疗效研究。
