In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure–activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

中文翻译：

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咪唑并[1,2- b ]哒嗪衍生物作为强效，选择性和口服活性Tyk2 JH2抑制剂的鉴定

与先前报道的一系列基于6-苯胺基咪唑并哒嗪的Tyk2 JH2配体形成鲜明对比的是，6-（（2-氧代-N 1-取代-1,2-二氢吡啶-3-基）氨基）咪唑并[1,2- b发现]哒嗪类似物显示出显着改善的代谢稳定性。2-氧代-1,2-二氢吡啶环上的N1取代基可以是各种烷基，芳基和杂芳基，但是其中2-吡啶基提供了大大提高的Caco-2渗透性，这归因于其形成分子内分子的能力。氢键。在C3位置进行的进一步的结构-活性关系研究导致鉴定出高效且有选择性的Tyk2 JH2抑制剂6在大鼠药效学模型中被证明可有效抑制IFNγ的产生，在大鼠佐剂性关节炎模型中则完全有效。